Phytanic Acid (Red Meat, Dairy, Seafood): Binds PPAR-α and RXR

'...Like all things come from the sun'
referencing all the food at the table,

daughter Natalie

ATB Sunset Girl

Courtesy: Youtube.com

Food, Sunlight and Nuclear Receptors

I've discussed RXR/RAR (carotenoids/ vitamin A receptor), VDR (vitamin D receptor) and PPAR-α (saturated fat/omega-3 receptor). These are a constellation of receptors found in the nucleus of all cells which control growth, maturation, reproduction, proliferation, apoptosis (cell suicide), autophagy (cell re-cycling) and inflammation.  Bioactive components of our food and hormone vitamin D from sunlight exposure (or organ meat consumption) bind and control nuclear receptors.

See prior posts:
PPAR -- Dagger in the Heart of CAD and all Chronic Conditions
Benefits of Grassfed Butter





Phytanic Acid Generates Carnitine

A recent study looked at the level of phytanic acid (PA), a
fatty acid found in red meat, dairy fat, and seafood which has activity on receptors known to control and regulate cancer, inflammation, triglycerides/cholesterol and even energy status in skeletal muscles. It may have several mechanisms for health regulation. One mechanism found is that phytanic acid is an agonist for several nuclear receptors including RXR and PPAR-α. I would not be surprised if it has affinity and binds other receptors as well.

We don't synthesize phytanic acid on our own; we can only source from food (animal based). Phytanic acid and its metabolite pristanic acid contribute to the activation of carnitine in peroxisomes which are later transported to mitochondria for fatty acid oxidation (burning and synthesis of energy, ATP). A lack of carnitine has been shown to lower mitochondrial processes and is significant factor in disease. Like phytanic acid, carnitine can mainly be sourced only from MEAT and seafood, not vegetables. We produce it but not very well. Many factors affect carnitine levels (kidney function, ACTH/cortisol, thyroid and diet. French authors write 'L-carnitine ensures regeneration of coenzyme A and is thus involved in energy metabolism. L-carnitine also ensures elimination of xenobiotic substances. Carnitine deficiencies are common.'  Photo credit: [1].

Do butter and bison do a body good?

YESSSSSS.




Chlorophyll Is Biotransformed into Phytanic Acid by Fish and Mammals

Apparently the chlorophyll content of the meat, seafood or dairy is what determines the amount of this important fatty acid, phytanic acid. 'PA (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid generated by the oxidation of the phytol side chain of chlorophyll in mammals. Because humans cannot release phytol from chlorophyll, PA in the human body comes from dairy products and ruminant fats in the diet' [2]. Shore-based food such as fish, salmon, molluscs, snails and krill have significant levels too since these consume smaller fish which consume chlorophyll from algae and green phytoplankton. Phytanic acid is also found in menhaden oils. There is a vague association with prostate cancer and levels of phytanic acid however the below authors discuss "the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk." Phytanic acid is metabolized in peroxisomes -- little fatty storage droplets where enzymes breakdown and metabolize fatty acids. Many of the metabolic breakdown products then go to the mitochondria to provide energy, intermediaries for the respiratory and energy producing complexes, and/or to absorb and quench ROS (reactive oxygen species, aka POLLUTION generated from energy production). If mitochondria are working awry, I suspect phytanic acid accumulation occurs because it is not being appropriately metabolized which could be genomic or post-genomic (Refsum syndrome).



Evolutionary Medicine: Mitochondrial Dysfunction

Many of our chronic diseases are a result of mitochondrial dysfunction -- our tiny nuclear power plants are on the 'blink'...often preferring glycolytic combustion over superior fatty-acid burning.  Mitochondria provide awesome power but can wreak untold destruction as well.

--compromised controls, directions and regulation for proper nuclear plant functioning (AMPK, cAMP)
--lacking power grid efficiency (leptin, insulin, cortisol, SIRT1, adiponectin, secretin, fertuin-A)
--malfunctioning or missing power plant cogs and parts (minerals, carnitine, AcCoA/pantothenic acid, omega-3)
--deficiency of buffering, recycling and containment of nuclear waste (coenzyme Q10/ ubiquinol)
--lacking managers and communicators (cell membrane stability and communication: omega-3 vitamins A B D E K2 thyroid cortisol estrogen progesterone DHEA pregnenolone testosterone saturated fat etc)
--excessive disruptions (high carb diets, endocrine disruptors, PCBs, heavy metals)





From Bacteria 4.5+ bya To Mitochondria

Other strategies to keep mitochondria free of breakdowns -- lifestyles and diet aligned with our evolutionary past from 4.5+ Billion Years Ago:

--lowish carbish (~150 grams or less net effective carbs I like...varying on goals, gut, adrenals, etc)
--saturated fat (~20% or more -- dietary or butt-sourced)
--low fructose
--low omega-6
--high omega-3
--high phytanic acid *wink*
--organic shore-based and grassfed/pasture-based fat and protein
--organic mineral rich plants, berries, nuts, meat/fish/fowl
--intermittent feast v. fast (seasonality)
--optimal hormesis status
--low pollution (air, water, mind)
--enjoyment of culture, music, arts, spiritual enlightenment
--engaging in community and social networks
--movement: rapid intense and languid continuous (yeah S*X counts)


Prior animal pharm:
You are only as strong as your weakest mitochondria...





Health and Food Connection

When I consume ghee (clarified butter), egg yolks, veggies, adequate starches and adequate grassfed beef, pork and lamb, I notice more and easy weight maintenance and improved muscle composition. Mental and physical performance are pretty excellent too. How do you break down food and its effects on mitochondria? Researchers are trying and it's a good thing....

Phytanic acid--an overlooked bioactive fatty acid in dairy fat?

Hellgren LI. Ann N Y Acad Sci. 2010 Mar;1190(1):42-9.

Abstract
Phytanic acid is a multibranched fatty acid with reported retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist activity, which have been suggested to have preventive effects on metabolic dysfunctions. Serum level in man is strongly correlated to the intake of red meat and dairy products and the concentration in these products is strongly correlated to the chlorophyll content in the feed of the cattle. Available data suggest that phytanic acid is a natural agonist for RXR at physiological concentrations, while it is more likely that it is the metabolite pristanic acid, rather than phytanic acid itself, that acts as PPAR-alpha agonist. Animal studies show increased expression of genes involved in fatty acid oxidation, after intake of phytol, the metabolic precursor of phytanic acid, but it is at present not possible to deduce whether phytanic acid is useful in the prevention of ectopic lipid deposition. Phytanic acid is an efficient inducer of the expression of uncoupler protein 1 (UCP1). UCP1 is expressed in human skeletal muscles, were it might be important for the total energy balance. Therefore, phytanic acid may be able to stimulate energy dissipation in skeletal muscles. Phytanic acid levels in serum are associated with an increased risk of developing prostate cancer, but the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk. However, certain individuals, with specific single-nucleotide polymorphisms in the gene for the enzyme alpha-methylacyl-CoA racemase, might be susceptible to raised phytanic acid levels. PMID: 20388135

Phytanic Acid (Cheese, Butter) Human RCT

How does phytanic acid perform as a drug? In a tiny Denmark RCT, this was tested.  The control group however also received phytanic acid therefore the results were substantially diluted out IMHO. Methods: In a double-blind, randomized, 4 wk, parallel intervention study 14 healthy young subjects were given 45 g milk fat/d from test butter and cheese with 0.24 wt% phytanic acid or a control diet with 0.13 wt% phytanic acid. The outcomes were positive and associate with metrics that indicate improved mitochondrial functioning (better insulin sensitivity, more fat oxidation, decreased glycolysis).   The lipoprotein changes were impressive but unfortunately the study was too small for meaningful stats. HDL-cholesterol increased by 10% in only one month.  No drug achieves this... or without killing patients or raising BG and diabetes (particularly Crestor).  Is it all phytanic acid?  I dunno...  The researchers enriched the test dairy products by feeding the cows more green material. Subsequently the omega-3 to omega-6 profile in test butter and cheese also improved. They discussed, 'The test butter with the highest content of phytanic acid, also had the highest content of α-linolenic acid [omega-3] and a lower n-6:n-3 ratio of about 1.8. This is in agreement with the higher proportion of clover and grass in the green feeding regime.'   Notwithstanding the beneficial numbers, butter and cheese have other proven bioactive food components which improve heart health, inflammation, insulin resistance and cancer risks, principally, cholesterol, vitamin A/retinol, saturated fatty acids including butyrate, omega-3, taurine (if raw), stigmasterol (if raw; Wulzen factor), folate (5-MTHF) and vitamin K2 (menaquinones).

Results:
(a) HDL increase 10% 
(b) Insulin reduction 15%
(c) TG reduction 22% 

References

1.Verhoeven NM et al. Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. The Journal of Lipid Research, Vol. 39, 66-74, January 1998. [Free PDF here]

2. Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid.
Tang XH, Suh MJ, Li R, Gudas LJ.
J Lipid Res. 2007 Jan;48(1):165-76.

3. Novel branched-chain fatty acids in certain fish oils.
Ratnayake WM, Olsson B, Ackman RG.
Lipids. 1989 Jul;24(7):630-7.

4. Oxidative stress and mitochondrial dysfunction in Fibromyalgia. MINIREVIEW.
Cordero MD, Miguel MD, Carmona-López I, Bonal P, Campa F, Moreno-Fernández AM.
Neuro Endocrinol Lett. 2010 Apr 29;31(2):169-173.

5. Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury.
Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P.
J Alzheimers Dis. 2010;20 Suppl 2:453-73.

6. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease.
Cordero MD, De Miguel M, Moreno Fernández AM, Carmona López IM, Garrido Maraver J, Cotán D, Gómez Izquierdo L, Bonal P, Campa F, Bullon P, Navas P, Sánchez Alcázar JA.
Arthritis Res Ther. 2010;12(1):R17. Free PMC ArticleFree text

7. Connecting the Dots: Molecular and Epigenetic Mechanisms in Type 2 Diabetes.
Goh KP, Sum CF.
Curr Diabetes Rev. 2010 Jun 9.

8. Fetal programming of atherosclerosis: possible role of the mitochondria.
Leduc L, Levy E, Bouity-Voubou M, Delvin E.
Eur J Obstet Gynecol Reprod Biol. 2010 Apr;149(2):127-30.

9. Spinal cord repair in MS: does mitochondrial metabolism play a role?
Ciccarelli O, Altmann DR, McLean MA, Wheeler-Kingshott CA, Wimpey K, Miller DH, Thompson AJ.
Neurology. 2010 Mar 2;74(9):721-7.

10. Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.
Desbois AP, Smith VJ.
Appl Microbiol Biotechnol. 2010 Feb;85(6):1629-42.

11. Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases.
Chakravarthy MV, Booth FW.
J Appl Physiol. 2004 Jan;96(1):3-10. [Free PDF here]

12. Glycolysis: a bioenergetic or a survival pathway?
Bolaños JP, Almeida A, Moncada S.
Trends Biochem Sci. 2010 Mar;35(3):145-9.

13. Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: a fertility first hypothesis.
Corbett SJ, McMichael AJ, Prentice AM.
Am J Hum Biol. 2009 Sep-Oct;21(5):587-98.

14. Liver fattening during feast and famine: an evolutionary paradox.
van Ginneken VJ.
Med Hypotheses. 2008;70(5):924-8.

15. Biochem pages http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html

16. Carnitine: an overview of its role in preventive medicine.
Kendler BS.
Prev Med. 1986 Jul;15(4):373-90. Review.

17. [L-carnitine: metabolism, functions and value in pathology]
Jacob C, Belleville F.
Pathol Biol (Paris). 1992 Nov;40(9):910-9. Review. French.

18. The metabolism of phytanic acid and pristanic acid in man: a review.
Verhoeven NM, Wanders RJ, Poll-The BT, Saudubray JM, Jakobs C.
J Inherit Metab Dis. 1998 Oct;21(7):697-728. Review.

19. Phytanic acid--an overlooked bioactive fatty acid in dairy fat?
Hellgren LI.
Ann N Y Acad Sci. 2010 Mar;1190:42-9.

20. Effect of dairy fat on plasma phytanic acid in healthy volunteers - a randomized controlled study.  [Free PDF here.]
Werner LB, Hellgren LI, Raff M, Jensen SK, Petersen RA, Drachmann T, Tholstrup T.
Lipids Health Dis. 2011 Jun 10;10:95.

21. Bioactive food components, inflammatory targets, and cancer prevention.
Kim YS, Young MR, Bobe G, Colburn NH, Milner JA.
Cancer Prev Res (Phila). 2009 Mar;2(3):200-8.

Paleo, Muscles, Homunculus, and Natural Selection

Paleo, Muscles, Homunculus, and Natural Selection

Body Fat Loss: Saturated Fat Kicks the Cr*pola Out Of Olive Oil

Loren Cordain Is Getting Into Coconut Oil

Yes. It is true.

O F

C O U R S E . . .


From Robb, "Cordain likes coconut oil, just as a mix to a standards paleo approach. " (adrenal post) Robb cracks me up.

Recall Dr. Cordain's recent publication with the history-making conclusion: 'In general, experimental evidence do not support a robust link between SFA [saturated fatty acid] intake and CHD [coronary heart disease] risk.' PDF click HERE Curr Treat Options Cardiovasc Med; 2009;11:289-301. I just had to repeat that. It's like... *haa* the SOUND OF MUSIC... [the hills are alive... *big winky*]




The Thing About Fat...

Let me quote another expert, Jeff Volek (see his testosterone study at end), "The Fate of Fat: You are not what you eat; you are what you do with what you eat. Eat fat with carbs you get fat, but eat fat with low-carbs and you get LEAN — and insulin is the switch that controls the fate of fat.

— Jeff Volek, The New Low-Carb Guru

This is true if you are eating olive oil, monounsaturated fats, omega-3 oil, canola oil, coconut oil or MCT oil. Cut out carbs. Esp GRAINS, LEGUMES and FRUCTOSE. FRUC F*CTOSE, the nastiest carb of them all. (If you are gonna have limited carbs... yams, sweet potatoes, red potatoes, and wild berries (higher in oils, lower in sugar) are slightly more acceptable.).

This holds especially true for those who are insulin resistant (HYPOTHYROID (e.g. FT4 and FT3 s*ck), lacking other major steroid hormones (adrenals, testosterone, estrogen, progesterone, adiponectin, vitamin D, and the previously or currently overweight/obese... like me, I used to be 50 lbs fatter *wink*).




Medium Chain Sat Fats and Coconut Oil

Coconut oil is ~100% saturated fatty acids.

No industrial toxic omega-6. No industrial trans-fats.

There are civilizations which consume high, ULTRA-high saturated fat diets (40-56%) of coconut oil with no elevated associations of cancer, heart disease, dental disease or chronic conditions (Tokelau, Sri Lanka).

Coconut oil and MCT Oil are thermogenic and produce ketones despite consuming carbohydrates.

Coconut oil is predominantly medium-chain triglycerides (only 28-30% long-chain). Coconut oil is 1:1:6 (C8:C10:C12). MCT Oil is ~1:1 (NOW brand) or 2:1 (MCT Gold); no lauric acid, C12.

Butter is ~1:2:2. (70% saturated, 20% monounsaturated)





Medium Chain Sat Fats and Breastmilk

Human breastmilk is 40+% saturated fatty acids and high in cholesterol. The role of medium chain saturated fatty acids in the early survival of babies cannot be overstated. Medium chain sat fats are anti-microbial and anti-fungal and promote ketosis which is anti-inflammatory. Lauric acid (C12) exhibits POTENT PROTECTIVE properties. I discussed earlier here (californication post). Colostrum medium-chain ratios are 1:10:60; HEEEYYYYGE GINORMOUS quantities of protective lauric acid. Mature breastmilk, as well, 1:10:40 (Gibson RA et al Am. J. Clin. Nutr. 34: 252-257, 1981.). Baby infant formulae contain negligible lauric acid (C12), omega-3 fatty acids or cholesterol (Giovanni et al Acta Pæd 83(s402):59 - 62). F*Q. Does that explain anything healthwise? Was not 'in fashion' to breastfeed in the 1970s (at least not in Nebraska). Commercial infant formulae actually contain a lot of TOXIC omega-6 LA (Oveisi et al Acta Medica Iranica, 44(4): 225-229; 2006.) The omega-6 LA is soybean and/or peanut oil (WTF?) (p.97, Natural toxicants in food By David H. Watson).




Ketones

How does Slo-Niacin (vitamin B3) work?

It hits the ketone receptors which is anti-inflammatory and subsequently leads to lower sdLDL, annihilation of the 'death band' LDL-IVb (the most dense and lethal), and raises the HDLs OUT OF THE ROOF.

Again, how do we produce ketones?
--low low low carb diet
--low low carb diet
--low carb diet
--physical low-moderate intensity activity > 1-2 hours (max HR 50-60%)
--fasting > 5-6 hours
--intermittent fasting 12-36 hour fasts (we all do this in the Paleo blogosphere, Crossfit, evolutionary lifestyles)
--starvation
--drink human breastmilk (just kidding)
--eat a lot of medium chain SATURATED fatty acids (coconut oil, coconut butter, MCT oil, coconut milk/meat, grassfed goat cheese/milk, grassfed butter oil (greenpasture.org), grassfed butter/ghee/cream, etc)


Apparently eating saturated fats 12% in the form of MCT Oil can double the body fat loss compared with equal portions of olive oil in near-obese (BMI ~29) men and women on a muffin diet. (Yes, high carb muffin diet.) These studmuffins still somehow lost body fat -- visceral and subcutaneous.

P H A T ! ! !



Saturated Fatty Acids Bind PPAR-Receptors

Saturated fatty acids are hormonal in action. They bind the potent PPAR series of steroidal nuclear hormone receptors (that drugs bind like Actos for diabetes and Tricor for low HDLs, high TGs). Food is our medicine. Recall saturated fats bind PPAR: prior post Lp(a) Dangerous At Any Level. Dietary carbohydates, on the other hand, degrade the PPAR receptors and raise Lp(a), inflammation, insulin and plaque progression.

Remember... medium chain saturated fatty acids are anti-aging (because they bind and activate PPAR and promote anti-inflammatory ketones)... it is a frequent component of the diets of many centenarian and long-living communities (Okinawan, Sardinian, Cretan, Belgium -- from goat milk and dairy products). Check this out again: Kaunitz. Medium chain triglycerides (MCT) in aging and arteriosclerosis. J Environ Pathol Toxicol Oncol. 1986 Mar-Apr;6(3-4):115-21.

In upcoming posts, my buddy NephroPal Dr. T will be reviewing the PPAR receptors. WOOO y-e-a-h !!

MCT Oil Kicks the Cr*pola Out of Olive Oil
St-Onge MP et al conducted a double-blind RCT comparing a low calorie, 'free living', 12% saturated fat/MCT Oil diet (medium-chain triglycerides, 50% of coconut oil) versus 12% olive oil diet for weight loss (Am J Clin Nutr. 2008 Mar;87(3):621-6). Free PDF click HERE. This is the only head-to-head trial I have found comparing MCT Oil and Olive Oil (another one used 24% saturated fat, 40% fat Canadian diet + 3% unesterified plant sterols + flaxseed oil which showed Pattern A 25.85 nm shifting versus 24% Olive Oil Pattern B mean peak LDL 25.45 nm in only 28 days; PDF click HERE, St-Onge MP et al 2003)

The MCT Oil and Olive oil diets were low-fat (naturally HIGH CARB) muffin diets.

The results were surprising.

Body fat recomposition.

Reductions in both subcutaneous fat and visceral fat which is highly associated with PLAQUE and heart disease.

One tablespoon of MCT Oil or coconut oil is ~ 15 grams of pure saturated fat. MCT Oil is liquid and can be heated (like olive oil) to a degree (though I wouldn't heat either). The participants in this study consumed about 1-2 tablespoons daily in a 4-month weight loss program, in the form of a muffin (10 grams) and cooking oil (8 or 14 grams).

DESIGN: Forty-nine overweight men and women, aged 19-50 y, consumed either 18 or 24 g/d (women or men, respectively) of MCT oil or olive oil as part of a weight-loss program for 16 wk. Subjects received weekly group weight-loss counseling. Body weight and waist circumference were measured weekly. Adipose tissue distribution was assessed at baseline and at the endpoint by use of dual-energy X-ray absorptiometry and computed tomography.

DIET INFO:
As part of the weight-loss program, the subjects were counseled to reduce their caloric intakes to 1500 kcal/d forwomen and 1800 kcal/d for men. Within this diet, all subjects received study muffins (either cranberry or blueberry; Krusteaz, Seattle, WA) that contained 10 g of their assigned oil and 8 or 14 g of liquid oil, for women and men, respectively, to incorporate into their foods during cooking. Therefore, all subjects received 12% of theirprescribed weight-loss energy requirements in the form of thestudy oil (18 g for women and 24 g for men). This level of oil was chosen because it was found to produce significant increases in energy expenditure (8). The subjects, along with the dietitian and clinical coordinator, were unaware of the oil each person was consuming. Muffins were given to the clinical coordinator in bags labeled with the subject’s study ID code and A or B to designate group. Oil was provided in opaque plastic containers, which were also labeled with the subject’s study ID code and A or B.

High Saturated 12% Fat for Weight Loss





High Sat Fat 12% Diet: 1.7 kg (~4 lbs) More Weight Loss After 4 MonthsThe authors showed a significant trend in body fat recomposition with employing MCT Oil as the primary fat in a free-living weight loss program. It is unknown what precisely the carb, protein or total fat intakes were other than ' low calorie'. This is a major limitation of this little trial. On the other hand one of the strengths was the use of technology (DEXA and CT scans) to accurately assess body fat. Few studies examine body fat recomposition with diet.

Results:
(1) both olive and MCT oil produced average 2.4-2.5 cm waist circumference loss (p=0.0001)
(2) MCT oil produced more body fat reduction 1.46% BF decreases v. 0.58% BF (p=0.0037)
(3) MCT oil produced more pronounced weight loss 3.2 kg (7 lbs) v. 1.4 kg (3lbs) (p=0.001)
(4) Visceral fat loss (intraabdom) 6.7-fold more (MCT oil: 8.85 cm2, NS, n=14 heavy drop outs)
(5) Subcutaneous fat loss (abdominal) 2.2-fold more (MCT oil: 24.76 cm2, NS, n=14 only due heavy drop out rate)






Higher Saturated Fat and Higher Fat Intake Associated With Higher Testosterone

See below diagram discussed earlier HERE. Volek JS et al has already showed that higher baseline testosterone has been highly associated with appropriate total fat (30+%) , protein intake (15%), saturated fat and fat composition (low LOW omega-6, saturated to monounsaturated ~50:50) (J Appl Phys 1997).

Higher the testosterone when:
--higher the saturated fat intake
--higher the overall fat intake
--protein not exceeding 15% (when carbs high)
--lower the PUFA/sat fat ratio, e.g. lower the PUFA, higher saturated fat intake
--lower the PUFA (e.g. canola oil, soy, saff, sunflower, peanut)



Grassfed Australian meat is 'balanced' -- whether it is mutton, lamb, beef or veal -- the fatty acid profile is ~50/50 for saturated to monounsaturated fatty acid ratios. Please see Table 4 (at the very end). Click HERE for PDF. Muscle meat is only 5-8% fat whereas 'fat meat' is about 40-60% fat (rest is collagen, water, proteins).

Eat meat. ALL of it. Fat meat and muscle meat.

Don't fear B E I N G A MEATHEAD. Or FATHEAD.




Testosterone: Male Fountain of Youth

We use testostosterone (topical cream and gels) for correcting lipoproteins and regression of plaque. Testosterone is great STUFF. Pound some saturated fats and do resistance training... the best way to naturally produce testosterone. I love Xfit. We do saturated fats + lifting/power exercises = Big 'T'. Testosterone is everywhere... I could lick it off the walls... *haaa*



Next Post:
Body Fat Loss: MCT Oil Kicks the Cr*pola Out Of Canola

Paleo and PPAR For Max Longevity

Mitochondria, DNA and Our Hearts

Nick Lane (author, Power Sex Suicide) also discussed how a small cost exists for the mitochondria to each contain, replicate, and maintain their own set of mtDNA. The costs must be worth the expense and final outcomes for cellular energetics, survival and, ultimately, longevity.

All day everyday 24/7 our bodies are correcting DNA damage, mutations and breakage in mitochondria and in the prime control center, the nucleus. DNA repair requires optimal functioning of crucial enzymes, critical hormone pathways, the presence of co-factors, and the absence of ROS and other oxidative stressors.

We employ ALL of these strategies at TYP for optimum regression of obstructive heart disease as detected, identified and calculated on EBT calcium scoring.


The TYP Program includes:
--Paleo eating (Read Dr.Davis' Cordain interview for TYP: HERE)
--Paleo exercise (eg, functional hypertrophy)
--Lp(a) identification and correction (17-25% of population carries)
--Homocysteine identification and correction
--Small dense LDL particle quantification and correction
--Hormone dysregulation and optimization to youthful levels (Vitamin D, Thyroid, INSULIN, DHEA, Melatonin, Estrogen, Progesterone, Testosterone, Cortisol, etc)
--Antioxidants with anti-inflammatory properties: High dose Omega-3, Niacin Vitamin B3 1-2 g/day, Vitamins ADE K1 K2 MK-7 MK-4, Vitamin C, Phosphatidylcholine, B-vitamins, Minerals Mg Zn Se etc, etc


Everyone who correctly identifies the 'problem' and correctly fixes the 'problem' achieves reductions in calcium scores in 1-3yrs. The side effects reported are: better senses (seeing, smelling, balance, reflexes), vitality, energy, weight loss, lower BP/glucose/resting pulse, improved cholesterol, glowing skin/hair/nails, etc. Besides plaque regression/stabilization and long-term heart protection (statins, optional *WINK*)... Oh BTW ... Maximum longevity, cancer protection, easy weight loss, body fat recomposition...looking H-A-W-T and Paleo-appealing *HA*, obesity-resistance, and being idiot-proof (ok... j/k!) are additionally guaranteed.

...Who doesn't desire a degree of that?

• Mitochondria in the human heart.
  Lemieux H, Hoppel CL. J Bioenerg Biomembr. 2009 Apr 8.
  Center for Mitochondrial Disease, Department of Pharmacology and Medicine, School of Medicine, Case Western Reserve University
  The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of
  (1) methods to understand mitochondrial function, with particular emphasis on integrated function,
  (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and
  (3) possible applications of this knowledge in the treatment of patients with cardiac disease.
  PMID: 19353253
• Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis.
  Puddu P, Muscari A et al. Cardiology. 2005;103(3):137-41.
  It is now widely accepted that oxidant stress and the ensuing endothelial dysfunction play a key role in the pathogenesis of atherosclerosis and cardiovascular diseases. The mitochondrial respiratory chain is the major source of reactive oxygen species as byproducts of normal cell respiration. Mitochondria may also be important targets for reactive oxygen species, which may damage mitochondrial lipids, enzymes and DNA with following mitochondrial dysfunction. Free cholesterol, oxidized low-density lipoprotein and glycated high-density lipoprotein are further possible causes of mitochondrial dysfunction and/or apoptosis. Moreover, in patients with mitochondrial diseases, vascular complications are commonly observed at an early age, often in the absence of traditional risk factors for atherosclerosis. We propose that mitochondrial dysfunction, besides endothelial dysfunction, represents an important early step in the chain of events leading to atherosclerotic disease.
• Mitochondrial integrity and function in atherogenesis.
  Ballinger SW, Runge MS et al.
  Circulation. 2002 Jul 30;106(5):544-9.
• The role of mitochondria in ischemic heart disease.
  Ferrari R.
  J Cardiovasc Pharmacol. 1996;28 Suppl 1:S1-10. Review.

Pimp Your PPARs! For Obesity Resistance

The family of PPAR nuclear receptors (NRs) are one of the ultimate controllers of inflammation, growth, proliferation, nutrient sensing, metabolism, and most importantly energy homeostasis. Remember, energy IN does not equal energy OUT. G-Flux post.

The medical literature only recently in the last 10-15 yrs exploded with information about these regulators of life. One of the newest elucidated pieces of the puzzle is that PPAR-Delta controls mitochondrial metabolism (uncoupling) in brown fat (our 'good' storage fat...keeps us warm when we shiver and many MANY other good things). The authors from the east coast remark, "Interestingly, the nuclear receptor PPARdelta not only mediates the actions of PGC-1alpha but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism... In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. " Pan D et al. Cell. 2009 Apr 3;137(1):73-86.


Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease.
Robinson E, Grieve DJ.
Pharmacol Ther. 2009 Mar 24.

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.
Chinetti G, Fruchart JC, Staels B.
Inflamm Res. 2000 Oct;49(10):497-505. Review.

Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: simultaneous activation of PPARalpha, PPARgamma, and PPARdelta.
Evans JL, Lin JJ, Goldfine ID.
Curr Diabetes Rev. 2005 Aug;1(3):299-307. Review.

Peroxisome proliferator-activated receptors and the control of inflammation.
Cabrero A, Laguna JC, Vázquez M.
Curr Drug Targets Inflamm Allergy. 2002 Sep;1(3):243-8. Review.

Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.
Touyz RM, Schiffrin EL.
Vascul Pharmacol. 2006 Jul;45(1):19-28. Epub 2006 Jun 16. Review.

Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.
Marx N, Duez H, Fruchart JC, Staels B.
Circ Res. 2004 May 14;94(9):1168-78. Review.

Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.
Guan Y.
J Am Soc Nephrol. 2004 Nov;15(11):2801-15. Review.

Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism.
Latruffe N, Vamecq J.
Biochimie. 1997 Feb-Mar;79(2-3):81-94. Review.

Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis.
Gouni-Berthold I, Krone W.
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Dec;5(6):513-23. Review.

Pleiotropic actions of PPAR gamma activators thiazolidinediones in cardiovascular diseases.
Takano H, Hasegawa H, Zou Y, Komuro I.
Curr Pharm Des. 2004;10(22):2779-86. Review.

Bone Marrow: Immunoprotective and Improves Endothelial Dysfunction

Chicken Soup. Do you love it?

Why?

Do you know scientifically and medically why it's so beneficial and therapeutic (better than a FLU SHOT)?



What satisfies the soul and combats colds, infections and vascular atherosclerosis (CAD, PVD, PAD, CVD, CKD)?

Bone marrow derived endothelial progenitor cells (EPCs)!!! From bone marrow.

(preferable organic, 80%+ grassfed, from Whole Foods or a reputable ranch)

Pharmacological approaches to improve endothelial
repair mechanisms.
Besler C, Doerries C, Giannotti G, Lüscher TF, Landmesser U.
Expert Rev Cardiovasc
Ther. 2008 Sep;6(8):1071-82. Review.
PMID: 18793110

Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived
endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-gamma agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.

The above seminal article suggests that bone marrow may hold the key to improving endothelial problems and inflammation. The astute authors suggest the below pharmaceuticals would be helpful. What are the food analogues if we had to 'deconstruct' these drug components they allude to? Would food be safer? Better? More efficacious? Yes... I belive so. Not just because your momma made it! :)

--Statins: How about fish oil? how about veggie-fibers? how about chol/sat fats? How about plant sterols (like in butter oil)?
--Angiotensin-converting enzyme inhibitors: How about Taurine, L-Arginine (like contained in nuts and seafood/meat?)? how about other essential proteins glutamic and aspartic acid, lysine, hydroxylysine and histidine?
--Angiotensin II type 1 receptor blockers: How about Glycine, Taurine?
--PPAR-gamma agonists: How about high dose EPA DHA fish oil ALA/flaxseed oil? how about Taurine/Leucine proteins? how about exercise/ IF/ starving occasionally? sat fats? how about CLA (like in meat and butter oil)? how about meat-derived Carotenoids which synergize PPAR effects? how about Lutein/eggs? Astaxanthin? Krill oil?
--Erythropoietin: How about eating b o n e m a r r o w ?


Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.
Das UN.
Lipids Health Dis. 2008 Oct 15;7:37. Review.
PMID: 18922179

Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins.
Paumelle R, Staels B.
Circ Res. 2007 May 25;100(10):1394-5. No abstract available.
PMID: 17525375


What does Bone Marrow contain which is so nutrient dense and fabulously fantastic?
--EPA + DHA
--Hormones: Testosterone, Estrogen, Progesterone, Human Growth Hormone
--Vitamin A D E K
--EPO (erythropoitin)
--Minerals: Magnesium, Calcium, Zinc, etc
--Saturated Fats
--Proteins: L-Arginine (which lowers BP in pre-eclampsic women), Glutamate, Aspartic acid, Lysine, Hydroxylysine and Histidine
--EPCs (endothelial progenitor cells) which improve our BLOOD VESSELS and promote better CIRCULATION AND BLOOD FLOW and healthier endothelium
--Serotonin, mood neurotransmitter (yes, SSRI antidepressants are highly associated with osteoporosis and nonvertebral fractures as we 've recently learned HERE and HERE and HERE); some people reported getting 'high' on bone marrow like marine biologist Dr. Dan, perhaps this is why? Marrow Madness and Its Hidden Secrets


Wow. My cat who can eat whole mice and their lovely bones knows what she's doing!

Peter's fans (eg, Anna of Against the Grain) have listed optimal bone feeding of cats HERE.

HDL2 = Quintessional Regression Particle and Ways To Maximize It

It's true. We do use some statins at TYP. Primarily they may have value until insulin resistant/hyperinsulinemia/Metabolic situations are improved via diet, hormone, vitamin D, and exercise/wt loss. Also they may have a role for FH (familial hypercholesterolemia) again until diet/lifestyles/vitamin D kick in.

Statins are by no means mandatory for regression or stabilization.

Or maximal health or lifespan extension.

In Dr. Davis' experience, in fact, a great majority of his patients experience statin intolerance and myopathy (muscle pains). Low grade muscle breakdown affects more individuals on statins than probably estimated in the literature. Most of these individuals likely have some kind of mitochondrial dysfunction and/or dietary cholesterol deficiency (and since statins BLOCK CHOLESTEROL SYNTHESIS, the drugs only exacerbate such situations). Muscles cannot function without...cholesterol and its downstream intermediaries...Including... Testosterone... Cortisol. Like 25(OH)D Calcidiol (vitamin D). Like estrogen!! Like DHEA. Like Pregnenolone.


In fact...all the HORMONES that make us what we are. Cholesterol is also a vital component of our BRAIN, myelin sheaths, nervous system, immune system and every cell's membrane.




Statins Indirectly Affect PPAR/Pleiotropy, Therefore Raise HDL2
Statins work marginally because they affect PPAR-alpha. (and other research shows PPAR-gamma as well HERE and HERE)

Recall, again, saturated fats and fish oil hit this receptor known as PPAR too. PPAR is the master controller of pleiotropic actions in our body. PPAR controls CETP reduction and PTLP maximization also.

Pleiotropic PPAR properties: endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, hemostasis/coagulation, vasomotor, cardiac muscle, anti-arrhythmic, and nervous system (brain and conduction pathways to the heart, organs, muscles)

Power up your PPAR...and you will attain immortality.




Not with statin monotherapy.
Clinical significance of pleiotropic effects of statins: lipid reduction and beyond.
Comprehensive lipid management versus aggressive low-density lipoprotein lowering to reduce cardiovascular risk.
Non-lipid effects of statins: emerging new indications.
Statin pleiotropy: fact or fiction?
Ongoing clinical trials of the pleiotropic effects of statins.
Beyond lipid lowering: the role of statins in vascular protection.
[Statins: intervention studies, facts and perspectives] "Questions still remain unanswered. To what extent do we have to lower LDL-cholesterol? What are the risks of an aggressive treatment with statins?"

In fact, a recent EBT trial by Raggi et al (2009 Atherosclerosis) lead to conclusions by leading cardiologists that LDL and LDL-reduction really have nothing to do with plaque.
Non-HDL cholesterol is strongly associated with coronary artery calcification in asymptomatic individuals.



If you have Lp(a), a toxic sticky lipoprotein that accelerates many diseases including coronary and vascular calcifications, then statins won't help you at all. In fact, anecdotally, certain high dose statins (like Lipitor) make Lp(a) concentrations higher. Studies estimate that 17-25% of the population are carriers of Lp(a). I estimate that a much greater percentage have this. In fact, all Metabolic Syndrome individuals appear to me to display very accelerated heart disease even if only a small amount of Lp(a) is present (for instance 6-20 mg/dl). What lowers Lp(a)? Everything that raises HDL2 naturally and non-synthetically. (Not statins, not Zetia, not Fibrates; Actos, a PPAR-gamma drug, a little; fish oil, fats, forgoing carbs/grains -- A LOT)
Increased lipoprotein(a) in metabolic syndrome: is it a contributing factor to premature atherosclerosis? Y E S

The below authors discuss: "bezafibrate as a pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin, ezetimibe, omega-3 fatty acids..."
Optimal management of combined dyslipidemia: what have we behind statins monotherapy?

In addition to niacin and omega-3 fats, how about other dietary fats/IF/strength training/anaerobic exercise/LC-diet?

*sigh* ....the best pan-PPAR activators...





HDL2 is Cardioprotective

We like HDL2 at TYP.

HDL2 is like wealth and health...You can never have too much balanced wealth or balanced health!

HDL2 is in fact an antioxidant and provides immunoprotection as well as cardioprotection. One of the labs ordered at TYP to assess health status is the NMR (or VAP) which separate out the lipoproteins by size and density and provide a 'count' of the absolute number of particles. The larger the particles, the better. HDL2 is one of the largest, most buoyant particles, and most desirable.

The more dense, the more deadly. Like dense fuddy-duds, we don't like dense particles. Read more at TYP here (members now; later free).

These are all good: HDL2, HDL1, LDL2, LDL1, Large-HDL, Large-LDL

Bad: sdLDL (small dense LDL), HDL3, Small-HDL, LDL3, Small-LDL



Jimmy Moore recently interviewed our beloved Dr. Davis. Jimmy's Large-LDL (and presumably HDL2's) are phenomenal!! He reported that he had virtually no small dense LDL -- it's all large -- the good stuff.

Jimmy's labs aren't dense!

Strong work Jimmy!!
http://heartscanblog.blogspot.com/2009/01/another-interview-with-livin-la-vida.html




Many things increase HDL2...


PPAR-alpha drugs, like Fibrates, do certainly hit PPAR -- but not in a natural configuation because these are synthetic/FAKE chemical entities. Fibrates artificially increase total HDL but have been shown adversely affect the particle sizing. They increase HDL3 and lower HDL2.

wtf... bad bad bad...

This explains why fibrate trials are like statin trials. So far only a very limited reduction in mortality, obstructive events and interventions have been demonstrated: approx only 15-25% reductions in CAD.

Remember, it's not the quantity of HDL you have, it's the quality of HDL subparticles -- large v. small.

You don't want... s m a l l. Or dense.

Like small muscles...where's the (sex) appeal?

What's the...point?


These researchers from Switzerland 'get it'... (sorta -- they still push pharmaceuticals *sigh*) "Recent findings suggest that the mechanism of HDL modification rather than a sole increase in HDL-C determines the efficacy of anti-atherosclerotic drug therapy. " Yes, these are my observations from the medical literature and at TYP. The ones who fail to achieve stablization or regression have VERY HIGH HDL-3 and VERY very low HDL-2. Their CAC progresses 10%+ annually and they are befuddled.
Modulation of high-density lipoprotein cholesterol metabolism and reverse cholesterol transport.
Marine lipids normalize cholesteryl ester transfer in IDDM.
Change in alpha1 HDL concentration predicts progression in coronary artery stenosis.



Statins work to regress plaque by affecting PPAR receptors in our body. Yes, LDL reduction is part of their novelty but by and large the regression pattern is secondary to its significant anti-inflammatory effects (via PPAR) and its plaque remodeling effects (via PPAR) and HDL-2 raising effects (via PPAR).

These encompass all the pleiotropic actions of PPAR.

PPAR is powerful.

(And who knows? Statins may help regress plaque by raising vitamin D blood levels as well. Yes, indeedddeeyyy, statins raise [25(OH)D] HERE and HERE.)

Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.
The effects of statins on high-density lipoproteins.
Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients.




Low-Fat, Low-Muscle, and HIGH-CARBS Lower HDL2

What degrades HDL2??
--AHA Low Fat/Step 2 diet -- makes you dense, your particles, I mean--Exercise deficiency or excessiveness (eg, overtraining)
--Lack of lean muscle tissue
--Preponderance of belly/visceral fat
--Excessive insulin
--Cortisol (stress)
--Carbs carbs carbs (high carb, grain-based diet)
--Soda, fructose (esp high fructose corn syrup), excessive fruit, grains, wheat (which also triggers stress responses), processed foods, cereal, etc
--Drugs/pharmaceuticals (Zetia, Lipitor high dose, statins high dose, Fibrates: Lopid/gemfibrozil, Tricor/fenofibrate)
--Insufficient dietary cholesterol, fish oil, monoun- or saturated fat intake
--Smoking
--Excessive alcohol (2-3 or more drinks for men; 2 or more, women)


What raises HDL2?
--The paleo prescription, eg, this blog, TYP and other resources--Niacin (see below)
--Intermittent fasting
--Generation of ketone bodies (low carb, mod-high prot/fat)
--Starvation
--Exercise (avoid excessive endurance training)
--Strength/resistance training
--Reduction in belly/visceral fat
--Reduction in insulin (eliminating wheat, reducing carbs)
--Tobacco cessation
--Elimination/moderation of alcohol
--Eating protein, esp Leucine, Taurine, etc
--Vitamin D (see Dr. Davis' blog)
--Carotenoids (astaxanthin, krill oil, seafood, grassfed meat, etc)
--Fish oil/EPA+DHA: supplemention, grassfed meat/dairy; fatty fish, mackerel, tuna, herring, hamachi, trout, cod liver oil, mollusks, krill, crustaceans, etc
--[If high inflammatory state: Ultra high dose 8-10 g/day EPA DHA fish oil for 6-18mos (Goal: fatty acid profile test, omega-6 to omega-3 ratio = 1.5)]
--ALA, monounsat fats: flaxseed oil, olive oil, nuts/seeds, etc
--Casein-free butter oil (rich in phytosterols, vitamin K2, CLA, short-chain and medium-chain saturated fatty acids, EPA+DHA and a bounty of other HDL-boosting nutritional factors); organic, grassfed ghee
--Eating some saturated fats (not TRANSFATS which are toxic to HDL2)
--Eating some CHOLESTEROL (via omega-3 eggs, seafood, grassfed meat/dairy, etc)






Niacin and HDL2

Remember niacin increases HDL2 by 200-300% (and reduces HDL3) in a 18-36 mos period of time... (niacin works indirectly on PPAR too)

Crestor only increases HDL2 by 21%??


Is that why Niacin (+low dose simvastatin) resulted in a 90% reduction in mortality and heart events in the unprecedented HATS trial?
Niacin-based therapy for dyslipidemia: past evidence and future advances.
Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia.


May it have anything to do with HDL2 subfractions increasing by 10 - 20 xxx with Niacin Therapy vs. Statin Monotherapy??!

Ten to twenty TIMES greater HDL2 increases...WOWO.

Why do statins fail to STACK UP when compared to niacin???

Billions of dollars have been pored into research (which is great and we're all grateful) but still they fail to regress/stabilize plaque as durably and effectively as Niacin, a common B vitamin which costs $12.99 for #150 tablets at Costco.

Why does Niacin trump all statins?

Niacin trumps Crestor, gorilla-statin... which can have gorilla effects on muscle soreness and kidney failure (via increases MMP-9 in the kidneys; unless one is taking fish oil/vitamin D which reduce systemic MMPs).




Fish Oil and HDL2

Of course, Fish Oil trumps statins in regression as well.

It's a dose dependent and time dependent effect.

(is more better? sorta. depends on your inflammatory status. if you have unstabilized CAD or an autoimmune disorder or cancer, you are inflammed.)
Here is one 1999 double-blind RCT in coronary male patients where low dose ~3 g/d EPA+DHA for 3 mos then switched to low, LOW dose 1.6 g/d EPA+DHA for 21 mos showed more regression than placebo . The Germans are always advanced with CAM (complementary alternative medicine).

The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial.

von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H.
Ann Intern Med. 1999

RESULTS: Pairs of angiograms (one taken at baseline and one taken at 2 years) were evaluated for 80 of 112 placebo recipients and 82 of 111 fish oil recipients.

At the end of treatment, 48 coronary segments in the placebo group showed changes (36 showed mild progression, 5 showed moderate progression, and 7 showed mild regression) and 55 coronary segments in the fish oil group showed changes (35 showed mild progression, 4 showed moderate progression, 14 showed mild regression, and 2 showed moderate regression) (P = 0.041).

Loss in minimal luminal diameter, as assessed by quantitative coronary angiography, was somewhat less in the fish oil group (P greater than 0.1).

Fish oil recipients had fewer cardiovascular events (P = 0.10); other clinical variables did not differ between the study groups.

Below: 4.5 g/d x6wks EPA+DHA resulted in a 74% HDL2 increase with a concomitant 19% decrease of HDL3-C
Omega-3 fatty acids selectively raise high-density lipoprotein 2 levels in healthy volunteers.

Below: 4 g/day x6wks DHA only related to 29% increased HDL2 (EPA 4 g/day only reduced HDL2 6.7%) in Obese Men
Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.


Below: 4 g/day x8wks EPA+DHA induced 40% increase HDL2 and reduction in HDL3 (this condition has genetically low HDL/high TG)
An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia.


Below: 6 g/d EPA+DHA x12 wks increased HDL2 47.8% (reduced HDL3 6.6%)
Dose-response effects of fish-oil supplementation in healthy volunteers.





Fish Oil and Genetics

Fish oil may be even more tremendously beneficial for those with apoE4 (eg, the Alzheimer marker). ApoE4 has also been implicated in the pathogenesis of heart disease and other vascular diseases. In the below trial, low dose fish oil 0.7g/day EPA DHA, compared with higher dose 1.8 g/ day, was also effective at lower TG and raising HDL, especially in men.

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.
Caslake MJ, Miles EA, Kofler BM, Lietz G, Curtis P, Armah CK, Kimber AC, Grew JP, Farrell L, Stannard J, Napper FL, Sala-Vila A, West AL, Mathers JC, Packard C, Williams CM, Calder PC, Minihane AM.
Am J Clin Nutr. 2008 Sep;88(3):618-29.

Happy Cows and Fish Oil

Here's an inspiring friend and buddy... Ms. Happy Cow like the rest of the happy cows in my neighborhood (see last photo from my camera). Everytime I run by one of the cows grazing on fresh clover and grass and absorbing full spectrum sunlight nearly all day, I have to resist the urge to put on... my dairy-maid outfit! And start milking! Here's the tribute to happy cows (and their DHA, EPA and CLA) which make ideas at the Animal Pharm (and my brain) possible...

This picture is courtesy of Bay Nature which showcases Mt. Diablo well in the background and more happy cows.

The benefits from dietary fat and protein sourced from grass- and clover-fed cows include hitting my favorite family of metabolic and proliferative switches in the mammalian kingdom... PPAR -- alpha gamma and delta! Not only does consumpation of dietary protein like beef and whey dairy protein activate mTOR and indirectly PPAR-delta, a natural fatty acid called conjugated linoleic acid (CLA) found only in the meat and milk of pasture-fed cows like the ones in the picture also directly binds PPAR receptors. Like many mysteries and secrets revealed by my MILFy buff girlfriends, CLA grows muscle to be defined, lean, and tight. Body fat significantly decreases and minimizes (but it aint a miracle -- you still need to work a little, ie lift and pump and eat right). What girl (or TYPer) wouldn't want that? Additionally CLA reduces cancer and reduces proliferation.

CLA is produced by the bacteria in the bellies of ruminants who consume grass or clover (not hay or grains).

Food sources of CLA (and Vits K2, D3, A, Butyric acid, EPA, DHA) :

--pasture-fed cowmilk (at most good health food stores: Organic Pastures $6.99/qt)

--raw pasture-fed cowmilk (see above --contains 'Wulzen Factor' = heat-labile stigmasterol which is an unsaturated plant sterol which lowers cholesterol)

--pasture-fed cowmilk cheese, butter, raw butter oil

--pasture-fed goat milk, dairy products

Protein sources with CLA (and DHA+EPA/aka 'fish oil'):

--pasture-fed beef

--pasture-fed lamb

--pasture-fed sheep

--pasture-fed goat

--pasture-fed bison, wild bison

--wild deer, elk, antelope

Of course I like CLA because also it potently binds and activates PPAR -- all of them. Alpha, gamma and beta/delta. This is why my muscles feel so wonderful and grow well (after like... some strain and pain... scrubbing those plaquey-toilets at home).

CLA raises muscle mass with resistance training in humans and reduces weight in the obese humans (and in rats):

• Lowery LM, et al. Conjugated linoleic acid enhances muscle size and strength gains in novice bodybuilders. Med Sci Sports Exerc. 30(5):S182, 1998.
• Pinkoski C, et al. The effects of conjugated linoleic acid supplementation during resistance training. Med Sci Sports Exerc. 2006 Feb;38(2):339-48.
• Tarnopolsky MA, Safdar A. The potential benefits of creatine and conjugated linoleic acid as adjuncts to resistance training in older adults. Appl Physiol Nutr Metab. 2008 Feb;33(1):213-27. Review.
• Blankson H, et al. Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr. 2000 Dec;130(12):2943-8.
• Gaullier JM, et al. Six months supplementation with conjugated linoleic acid induces regional-specific fat mass decreases in overweight and obese. Br J Nutr. 2007 Mar;97(3):550-60.
• Gaullier JM, et al. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr. 2005 Apr;135(4):778-84.
• Gaullier JM, et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr. 2004 Jun;79(6):1118-25.
• Risérus U, et al. Conjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial.
  Int J Obes Relat Metab Disord. 2001 Aug;25(8):1129-35.
• Eyjolfson V, et al. Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Med Sci Sports Exerc. 2004 May;36(5):814-20.
• Liu LF, et al. Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice. Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1671-82.
• Park Y, et al. Changes in body composition in mice during feeding and withdrawal of conjugated linoleic acid. Lipids. 1999 Mar;34(3):243-8.

Muller et al studied how if human vascular cells also may carry CLA as ruminant tissues do... guess what he found? Müller A, et al. Detection of conjugated dienoic fatty acids in human vascular smooth muscle cells treated with conjugated linoleic acid. Biochim Biophys Acta. 2005 Dec 15;1737(2-3):145-51.

"Conjugated linoleic acids (CLA) have attracted scientific interest due to their potential beneficial effects on atherosclerosis. Recent studies demonstrated that conjugated metabolites of CLA are found in tissues of CLA-fed animals and cultured cells treated with CLA. This observation has gained in importance since it has recently been shown that these metabolites of CLA exert specific biological activities...Examination of fatty acid composition of total cell lipids ...revealed a significant isomer-specific formation of conjugated metabolites of CLA such as CD16:2, CD20:2 and CD22:2 in human coronary artery smooth muscle cells treated with various CLA isomers. Different CD16:2/CLA ratios between various CLA isomers as observed in the present study indicate that fatty acid metabolism is differently affected by the configuration of the double bonds. In conclusion, the observation from the present study suggests that the effects of CLA in vascular cells might not only be mediated by CLA itself but also by its conjugated metabolites."


Of course synthetic CLA is artificially created with hydrogenated cheap industrial veggie oils which is not likely to be as beneficial (longterm) as naturally derived CLA from whole foods.

RELATED LINKS:

• Higher concentrations of vitamin E, CLA, long change omega-3 fatty acids in pasture fed cow milk. Leiber F, et al. A study on the causes for the elevated n-3 fatty acids in cows' milk of alpine origin. Lipids. 2005 Feb;40(2):191-202. PMID: 15884768


• Grain (corn) feeding lowers CLA and content of other important nutrients like Butyric acid (4-carbon fatty acid) in the fat of cow milk. Stockdale CR, et al. Influence of pasture and concentrates in the diet of grazing dairy cows on the fatty acid composition of milk. J Dairy Res. 2003 Aug;70(3):267-76. PMID: 12916820


• Beef meat considered a source of 'omega-3s' EPA/DHA when pasture fed. Mann NJ, et al. Feeding regimes affect fatty acid composition in Australian beef cattle. Asia Pac J Clin Nutr. 2003;12 Suppl:S38. PMID: 15023647


• Ponnampalam EN, et al. Effect of feeding systems on omega-3 fatty acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on human health. Asia Pac J Clin Nutr. 2006;15(1):21-9. PMID: 16500874

Atheroma Regression 101 -- Focus on HDL

Dr. Steve Nissen certainly deserves some respect. Not only does (a) he stick his neck out for the heart protection of Americans and (b) endorses CAC scoring/EBT for plaque/atheroma validation, he supports regression data in alignment with the Track Your Plaque goals for regression 60-60-60-60 already established by Dr. William Davis MD FACC. In a recent post-hoc analysis he reviewed data pooled from 4 major trials (ASTEROID, CAMELOT, REVERSAL, ACTIVATE) where plaque was diagnosed with angiography and tracked via IVUS over ~18 months (n=1455). The plaque volume % (PAV) decrements tracked well with i-n-c-r-e-a-s-i-n-g HDLs. And even more substantial reductions in total atheroma volume (TAV) were seen with more dramatic increases in HDLs.

The average 'regression' lead to an average 0.5 increase in PAV (2% increase and wide SD=15.7%) and a total atheroma volume reduction of 2.4 mm3 (only -0.2%; wide SD=17.4%). The authors note that in the ACTIVATE trial nearly 90% of patients were already on a statin and in fact their LDLs were less than 100 at baseline. Benefits for plaque stabilization and regression may have already been reaped prior to initiation for this sub-group which makes up 1/4 of the study. The duration of statin therapy was unknown.

These changes (avg plaque change: + 0.5)) were observed with the combination:
(1) LDL reduction (study avg=87.5 mg/dl final)
(2) increased HDL changes (the 'higher the better' with avg change=7.5% --the greatest regression was associated with HDL increases of 40% and HIGHER)
(3) lower LDL/HDL ratio (study ratio=2.1)

Average apo B was also significantly reduced from 131 mg/dl to 95 mg/dl (36% reduction) which was statistically correlated to changes in both PAV and total atheroma volume (p less than 0.001). The regression graph (see Figure and graph areas where PAV change is less than zero) lines up with TYP standard goals 60-60 for LDL and HDL.

TYP Goals (standard):
-LDL-C =60 mg/ml (see above arrow; higher?? see hard cardiac events)
-HDL-C = 40% increase to 60 mg/ml (study baseline avg = ~43 mg/dl; sorry--arrow wrong!)
-LDL/HDL ratio = 60/60 = 1.0


This regression data certainly emulates TYP to me!! The results truly seem to demonstrate the '60/60' vision...of a regressionist!! Like our beloved Dr. Davis :)



Often Dr. D achieves lipoproteins even beyond his standard goals. Many who follow TYP obtain LDLs lower than 60 and HDLs far higher than 60. Of course TGs fall far lower than 60 as well (often 40s) and of course apo B naturally drop as well (I'd conjecture less than 60).

So perhaps standard goals may be revised for those with 'stubborn' plaque.... based on this new information.

Who might benefit? The analysis showed that independent predictors of change in PAV were baseline PAV, the presence of diabetes and/or hypertension. For total atheroma volume, independent predictors of change were baseline TAV and BMI.

Refer to the L-sided endpoints of each graph in the Figure. The regression data certainly supports substantial size reductions of plaque occur with further improvements in LDL and HDL. HHHhhhhmmm..... Therefore, based on reported values of TYP'ers who experience regression/stabilization, the below standards may apply. At TYP, we are not LDL-centric. Small-LDLp centric extremely so, but never accuse us of LDL-mania...

Ultimate TYP (hypothetical) for Ultimate Regression:

-LDL-C = 60 mg/dl
-HDL-C = 60-80s mg/dl
-TG = 40-50 mg/dl
-TG/HDL ratio = ~50/83 = 48/80 = ~40/67 = 0.60
-LDL/HDL ratio = 60/80 = 0.75

-(? 60-60-60-0.60 ===> LDL-25(OH)D-apoB-TG/HDL-ratio)


The most significant contribution that Nissen made I believe was actually not mentioned in his comments or conclusions. In fact his conclusions from the data differed from mine regarding reduction of clinical events at 18 months and less than 18months after starting a Statin (or for ACTIVATE subjects, statin duration prior to the study longer than the rest of the test subjects). If you review Dr. Nissen's Table 6 below, you'll notice an interesting phenomenon. The best reduction of clinical events outcomes (obstructed events or events requiring re-vasc) supports actually a higher LDL-C (calculated) v. lower LDL-C at time 18 months for the group with a 'good' healthy HDL increase and LDL surprisingly g-r-e-a-t-e-r than average LDL=87.5 mg/dl.... hhhmmm... what could be going on here...? May stabilization (which translates best to reduced revasculariazations) require a little increase in % atheroma volume (though total plaque mass show decreases)?? The data may suggest this (see below 2 duplicated Table 6's).


Dividing out the study pop into 4 subgroups compared responses related to HDLs (and apo B) which appear to exhibit the highest association with clinical events. Perhaps when LDL is less than 87.5 mg/dl, the presence of small LDL still plays a HUGE role? Perhaps those individuals who experienced the most substantial INITIAL improvement in HDLs also had the greatest shift from Pattern B to Pattern A? Perhaps this shift explains the reduction in revascularizations (p=0.07) since these occur at higher frequency 6-12 months after a previous PTCA/stent. Rates of prior percutaneous intervention were in fact high in the study groups (71%, 30%, 81%, n/a). Could the first sub-group have had some plaque shrinkage but were still in the early stages of plaque-remodelling? Perhaps the first sub-group contained two distinct stages of regression -- one early (not stabilizied yet) and one late (stabilization + regression). Of course, the unstabilized will increase clinical events, especially if the presence of small LDL has not been addressed (ie, fish oil deficiency, vitamin D3 deficiency, carb-overloading). It only takes a few events or revascularizations to affect the data. Maybe there is a period of even 'fluffiness' of plaque (surface, core/internal) right before it stabilizes and regresses... synonymous with the changes occuring in the arteries where small LDL is shifting toward buoyant, more benevolent particles? Perhaps it's a phase... and we only have part of the snapshot...

What an amazing picture to behold though... Regression t-r-a-c-k-e-d in such a large population!

Let's thinc again... Perhaps the LDL-calculated based conclusions are bunk? Is LDL-calcuated really the 'lousy' cholesterol???

It's too bad the large trials failed to VAP or NMR the lipoproteins (or at least failed to report smLDL-particles).




Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K, Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. (Full PDF here)
Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.
JAMA. 2007 Feb 7;297(5):499-508.
PMID: 17284700

The conclusions that I draw from the data (though apparently non-statistically significant; who the heck was the statistician) is that human clinical events data support an approximately 50%+ decrease in revascularization-events in the group with higher LDL-C (read: lower small-LDLp) when compared with those with lower LDL-C (read: still high small-LDL in a subset of patients which may have contributed to higher clinical events requiring revascularization).

When plaque stabilizes, the echogenicity increases on ultrasound. Does this also contribute to mildly increased plaque volume? Perhaps? When you get a scab on a traumatic wound, does the scab appear thicker and heavier (esp if you're swimming!) before subsequently falling off after new pink epithelium grows?

Dr. Nissen notes:

"Greater percentage increases in HDL and lower levels of LDL (NOT) and LDL/HDL ratio in patients during treatment with a statin resulted in atheroma regression (BUT NOT HUMAN CLINICAL CAD/CVD EVENTS)...

...This is, to our knowledge the first time that increases in HDL levels have been shown to be an independent predictor of beneficial outcome with statin therapy."

Now Nissen is erudite.

He also looked at 'substantial' responders, meaning those with massive regression (b/c the above data otherwise makes little sense -- to statinators). And HDL-cholesterol undoubtedly must be raised for regression. Could Crestor have higher affinity for PPAR receptors or indirectly affect PPAR more?

His results when looking from a different perspective comparing Non-Responders v. Responders is even more intriguing than the above data. And holds more answers to the key to SUBSTANTIAL REGRESSION. Additionally this data is in direct compliance with TYP principles 60-60-60. Responders were assigned if significant volume/PAV% relative reduction of 5% or greater regression occurred (?about twice or more the average amount?).

Responders comprised 34% of the study population (n=370 were they all Crestor/ASTEROID??). Looking at this data (see Table 5 in the PDF), you'll notice immediately that huge increases in HDL and apo B occurred and likely lead to the dramatic PAV reductions in responders. In fact the difference between HDL improvements between Non-regression subjects and Substantial-Regression subjects was nearly 58% (6.5% v. 10.3%; wide SD 17.2%)) Remember average HDL change was 7.5%. Wow. I bet some of these individuals with massive plaque regression hit the TYP goals of 40% increase to HDL=60 mg/dl (perhaps combined with exercise/diet changes) and TG=60 mg/dl. For apo B, there was also wide variation apparently among the subjects, but also apo B dropped substantially by 40.9 mg/dl to an average of 90.1 mg/dl in the Regression group (almost close to TYP less than 60-70 mg/dl goals!). The median change was 34.8% (SD wide 25.0%) whereas the Non-regression median apoB change was only 25.7% (SD 24.8%).

Wouldn't it have been interesting to see if the Responders had reduced clinical events? Instead of just breaking down LDL-subsets?


Does Nissen know that Statins substantially affect PPAR???! And the regression benefits for regression may be attributed more strongly to PPAR than LDL? Evidently not... though he mentions VA-HIT and Helsinki Heart (he forgot DAIS) which are primary and secondary prevention trials that demonstrated reduced mortality and events with fibrates (PPAR-alpha agonists) especially in the diabetes subsets (ie, high insulin).

We discussed how statins both bind and indirectly affect plaque-mac PPAR earlier here.

The many pleiotropic benefits of statins are related to reduction in inflammation via Macrophage's PPAR activation at the plaque level in damaged endothelium:
--reduction in CRP
--plaque stabilization
--reduced oxLDL in plaque
--atheroma regression


Does this suggest that PPARs regress plaque...?

I do believe so


How do statins causes lipoprotein benefits via activation of Mac PPAR a and PPAR g ?

Nissen saw no significant contribution of statins on TGs on changes in PAV but TGs were statistically associated with improvement. The regression was attributed most strongly to vast HDL increases he reports (and to dramatic apoB and small-LDLp reductions which he didn't really address in the text) .

PPAR activation leads to these lipoprotein benefits:
--reduction in small-LDLp
--reduction in apoB
--reduction in TGs
--INCREASES IN HDL-C


So statins are like PPAR agonists? So statins work like food and food sensors?

What food item works the best as a PPAR agonist? What's my favorite supplement?




Bays et al nicely describes the benefits, MOA, and clinical implications of omega-3 fatty acids. Next to the NIACIN-king... fish oil R-O-C-K-S. Fish oil raises HDLs by an impressive 11-14% in clinical trials. The benefits are dose related, the higher the dose, the higher the HDLs. The lower the baseline HDL, the higher the potential increases.

Fish oils benefits for regression are three-fold:
(a) reduced systemic inflammation via PPAR
(b) increase HDLs via PPAR
(c) reduce apoB and insulin via PPAR

Another dimension of fish oil CAD benefits is its electro-stabilizing effects on cardiac conduction and prevention of arrhythmias.

Bays HE, Tighe AP, Sadovsky R, Davidson MH.
Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
Expert Rev Cardiovasc Ther. 2008 Mar;6(3):391-409. Review. (Full PDF here)
PMID: 18327998


Synergistically, Statins and Fish oil can work together to stabilize and regress plaque. The authors eloquently review how both have separate mechanisms which complement and accelerate the conversion of small-LDLp to IDL than to large non-atherogenic LDL.

Synergism... I like that...

What are other mechanisms to raise and maximize HDL?

Depending on the degree of plaque, the more the below are achieved, the greater the increase in HDLs...
--stop all wheat
--stop all grains
--minimize all fruit
--stop all HFCS garbage
--consume adequate high-quality protein 1 g/kg
--consume Hg-free seafood
--consume EPA+DHA
--consume nuts/seeds
--intermittently fast
--exercise, some HIT (high intensity training -- only after medical clearance -- of course)
--get lean muscle mass
--abdominal fat loss
--decrease IR (see above)
--tobacco cessation
--maintain good sleep

-BG