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Eden: Liver = Heart

Posted Oct 01 2008 4:30pm

Which Samurai with his spunky
spiky haired-side kick deftly defeats PLAQUE?
Courtesy of

Eating is definitely a sensory activity that starts with the brain-- have you heard that saying 'eating with your eyes'? Have you ever given your liver much thought while you consuming your meals or snacks? Ever wonder where does the food go before it hits the bloodstream?

In fact, the human liver is the largest internal organ comprising of 3 lobes and receives all the blood after a meal from the stomach and intestines via the portal vein. How does the body sense abundance in the environment?

Through the eyes? No... ye ol' LIVER...

If food (quantity and quality and composition) serves as one of the cues from our external physical environment, then the liver and the PPAR receptors located there there are the sensors of the degree of energy abundance/scarcity. What elements are essential for life outside of air? Food -- water -- light.... Similarly, what senses light? It is likely that VDR (vitamin D receptor) plays an equally important and parallel role. Abundant sunlight for most countries near the equator typically signals abundant food/energy. Vitamin D does rev up energy, productivity, and *hey* fertility! Naturally it follows that the skeletal muscles are the sensor for muscle movement and certainly the PPAR receptors in skeletal muscle do a great deal to command the balance of energy demand and supply/thermogenesis.

What might the holy trinity of human energy look like? mTOR--PPAR--VDR ? How might it have been shaped in our 'evolutionary heritage'...??? (thanks for the term Grey Whale!)

Well, we certainly know a lot of about what contribute's to this trinity's dysregulation...

  1. Lean-muscle-and movement-deficiency

  2. Wheat/grains consumption (including excessive fruit/FRUCTOSE too)

  3. Vitamin D3/sunlight deficiency

Even statins improve this trinity... by activating (!!) PPAR ... This special anti-inflammatory and MMP-stabilizing effect occurs specifically at the macrophage level and for plaque, this translates directly to the surface, volume and core of plaque atheroma. The pleiotropic benefits of statins can now be attributed to a direct activation of PPAR on macrophages via the MAPK pathway.

Paumelle R, Staels B.Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins.Circ Res. 2007 May 25;100(10):1394-5. No abstract available. (see Diagram: Cross-talk of statins/ PPARs in the antiatherogenic properties of statins --PDF here) PMID: 17525375

Yano M, Matsumura T, et al.Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res. 2007 May 25;100(10):1442-51. PMID: 17463321

Paumelle R, Staels B, et al.Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway.
Circ Res. 2006 Feb 17;98(3):361-9. PMID: 16397146

Landrier JF, Thomas C, et al.Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.
J Biol Chem. 2004 Oct 29;279(44):45512-8. PMID: 15337740

Verreth W, De Keyzer D, et al.Rosuvastatin (INCREASES mRNA of PPAR-GAMMA AND) restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice. Br J Pharmacol. 2007 Jun;151(3):347-55. PMID: 17384667

Roglans N, Sanguino E, et al.Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002 Jul;302(1):232-9. PMID: 12065722

Sanguino E, Roglans N, et al.Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br J Pharmacol. 2005 Aug;145(7):853-61. PMID: 15912134

In historical texts (ie, the Bible), the liver was actually considered 'the heart.' And, in the ancient days, harm to the liver was actually worse than to the heart. How were they so wise (without high tech ALT/AST tests or abdominal u/s) ??! For warriors, the liver was an easier, bigger target to hit than the smaller heart. We often neglect this fantastic vital organ. Interestingly, when the trinity is disrupted, this organ becomes metabolically deranged even before the heart.

Here are the liver's awesome functions and roles:
  • first pass effect = all blood during digestion is maximized to flow through the liver. Perhaps this is the role after meal apertifs, Greek grappe or (!!YUM)aged port have -- they relax, increase Vagal communications to the GI system to further shunt blood flow to the stomach and intestines for digestion

  • cytochrome P450 -- detox's, purifies everything we eat including plant toxins and exogenous chemicals like drugs (explains why oral estrogen can worsen HDLs whereas topical/transdermal estrogen improves and RAISES HDLs by bypassing the liver route)

  • cytochrome P450 activates and processes everything we eat including all food components and neutraceuticals (vitamin D3, essential fatty acids, protein)

  • energy sensor (carbs, fats, proteins, alcohol, caffeine, etc -- all my favorite food groups)

  • ultimate CONTROLLER in the financial as well as airtraffic sense because the liver contains the highest concentration of PPAR receptors: alpha, gamma, and D-E-L-T-A (aka beta)

  • producer of lipoproteins which are the energy 'traffickers' for the immune system, skeletal muscles and even brain (which relies on ketones/fatty acids when blood glucose (BG) is naturally lower)

  • producer of TGs -- the lipoprotein fraction where carbohydrate-energy (dietary carb +/- fat) is bundled into for transport to the rest of the body (including clogging up the heart tissues and arteries). Recall that TGs is the second RISK FACTOR most highly associated with plaque. First is... fasting insulin levels.

  • regulates and synthesizes cholesterol which is the template of EVERY nuclear steroid (and some aromatases, desaturases, and cyt P450 are under the control of VitaminD3) -- steroids like testosterone, estrogen, cortisol -- and composes the structural backbone/shell of every cell in our body and in particular the brain/nervous system which is comprised nearly entirely of cholesterol and fats (should pregnant moms eat 'low fat'? do pregnant moms want brain-deficient, cognitively-challenged children?)

  • vitally crucial for producing mannose-binding lectin (MBL) which is an activator of our host defenses in the innate broad-spectrum non-specific immune system (which fights virus, bacteria, and other foreign invaders including FRUCTOSE attached to our own cells) ; 'fruct-osylated-cells' aint good... sounds pretty bad eh? indeed VERY BAD

  • first organ to become unhappy when carbohydrates are excessive ('fatty liver', NAFLD, NASH, etc); see diagram above

  • one of the most prized organ meats and delicacy (in indigenous cultures and our household with a little soy sauce and honey) highly valued for its nutritional content of metabolically-active and heart protective Vitamins K2, D3, A, E and other essential nutrients and minerals.

In a recent Circulation article, researchers are elucidating the important role of Von Willebrand factor (VWF) in acute coronary syndromes (ACS).

"von Willebrand factor (VWF) plays a pivotal role in platelet adhesion and aggregation at sites of high shear rates (eg, in coronary arteries that have stenotic or ruptured atherosclerotic plaque lesions). Numerous studies have investigated the relationship between VWF plasma levels and thromboembolic cardiovascular events. In contrast to the rather weak association in the general population, in patients with preexisting vascular disease, VWF is significantly predictive for adverse cardiac events, including death. Likewise, VWF typically rises during the course of acute coronary syndrome, and the extent of this VWF release is an independent predictor of adverse clinical outcome in these patients. Various lines of evidence indicate that VWF is not only a marker but also actually an important effector in the pathogenesis of myocardial infarction. This central role of VWF in thrombogenesis has made it a promising target for research into new antiplatelet therapies that specifically inhibit VWF (AND BLAH BLAH BLAH... DRUGS)..."

How is VWF related to the thrombosis and clotting effects in our blood vessels? Obviously there is a healthy balance. Those with VWF deficiency have bleeding gums, mucus membranes and bleeding under the skin.

Is the liver involved? It appears the liver is involved in everything!

Platelets require the intervention of a blood protein known as Von Willebrand factor (vWF), which facilitates platelet adhesion to the sub-endothelial matrix of damaged, exposed endothelium. When the liver is aged, i.e. metabolically/oxidatively affected, a corresponding increase in vWF occurs intrahepatically (see below). Can this also occur systemically? To the coronary arteries? Or carotids? If we keep the endothelium of one of our most vital organs, the liver, happy... clear and uncongested, then endothelium elsewhere is likely to be protected as well. Prevent hardening of the liver, and you'll prevent hardening of the arteries. Reverse liver damage, and you'll reverse artery damage.

Timing as usual makes a difference. Even young-obese children are displaying NASH/NAFLD and early changes in myocardial structure such as diastolic dysfunction/heart failure.

The below changes including the increase in vWF from the endothelium in the liver blood circulation sounds a lot like instigation of arteriosclerosis of the liver...

Love your liver... and both hearts will appreciate it...

Ways to maximize liver function and productivity:
** Movement, play, movement, work, intervals of intensity, play, grow your muscles... especially with our children. 'The family that plays together, stays together...and doesn't have heart attacks together,' quoted by a member at my CF gym
** Complete Wheat/Grain avoidance and minimal fruit
** Adequate vitamin D3 (achieve: 25(OH)D 60-70 ng/ml)

Old age and the hepatic sinusoid.

Anat Rec (Hoboken). 2008 Jun;291(6):672-83. Le Couteur DG, et al.

Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up-regulation of von Willebrand factor and ICAM-1 with reduced expression of caveolin-1. These changes have been termed age-related pseudocapillarization (SOUNDS TO ME LIKE CALCIFICATIONS AND ARTERIOSCLEROSIS). The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products. Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age-related (I.E. METABOLIC DEREGULATION) changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age-related diseases.
PMID: 18484614

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