Liam Butler interviews Professor Robin Fraser

Liam Butler interviews Pathologist, Emeritus Professor Robin Fraser

05 August 2014

Liam Butler

Emeritus Professor Robin Fraser ONZM, BSc, MB BS(Syd), PhD(ANU), MD(Otago), FRCPA keeps his interest in the liver sieve as visiting professor to the University of Sydney. This work is directed by Prof. David Le Couteur (Centre for Education and Research on Ageing at Concord Hospital and the ANZAC Institute of Medical Research) Robin is a collaborator and an advisor to this exciting work.

Question.

"Professor Fraser, you explain that the liver is like an oil refinery and works best with regular maintenance, which means not drinking alcohol for a few days each week. For older people what are the benefits of adhering to this advice and what are the risks if they choose to ignore it?"

" Not drinking a few days each week is excellent health advice, not only for the elderly but for younger adults as well. It is right in line with the Health Promotion Agency's low-risk weekly drinking guideline of no more than 10 standard drinks for women, 15 standard drinks for men, and at least two days of not drinking. I also believe "Research Saves Lives" (our CMRF slogan) and attach our research findings for your readers to consider.

"THE LIVER SIEVE"

Nature's Nanotechnology, Balancing Health and Disease

As an elderly pathologist I pioneered in this concept and now have the privilege of being an enthusiastic colleague of a band of world-wide scientists and clinicians exploring related biological pathways. We research from the most southerly medical faculty (Otago) to the most northern (Tromso). By examining our concept, we together shall attempt to answer the question .The 2 kg human liver has multi-functions, reminding me of an oil-refinery (instead of crude oil to petrol to LPG to plastics...think of food to glucose, proteins, fatty and amino-acids, cholesterol, and energy). This major metabolic organ processes two litres of blood a minute from the gastro-intestinal tract and body.

The hepatic circulation of the portal vein (from the gut) and hepatic artery (from the body) resembles two intertwining tree trunks with many branches and about one million leaves. Each lobule (leaf) contains about one thousand tiny blood vessels (capillaries or sinusoids) lined by gossamer-thin porous walls (fenestrated endothelium) perforated by a myriad of 100nm diameter pores. This endothelium has an area of about a tennis-court around the billion in-parallel capillaries. It is perfect as a porous interface sieving substances to and from the blood and the encircling hepatocytes (liver cells). We have demonstrated its ability to separate chylomicrons, the largest of lipoproteins (triglyceride-rich chylomicrons after high fat diets ) from their smaller triglyceride-depleted but cholesterol-rich remnants. Thus we first described the "Liver Sieve" (1975-8).

Sieving complimented our previous finding that chylomicrons in both rats and rabbits increased in size following high fat diets (1968). We thought chylomicron-size might influence hardening of arteries.However although the nascent chylomicrons reaching the blood stream in both species are of similar size, only the rabbit,(not the rat) is sensitive to dietary cholesterol, so developing atherosclerosis. Why?

In 1983 we confirmed that the NZ white rabbit's liver sieve fenestrae were only 50nm in diameter (rat's were 100nm) explaining their susceptibility to dietary cholesterol because 50nm fenestrae are too small to remove cholesterol-rich remnants. However we later found that with nicotine in rats blood, with levels resembling human smokers, their fenestrae decreased from 100nm to 50nm to become,as in rabbits, hypercholesterolaemic(1988) Short-term alcohol in rats dilates fenestrae leading to larger than usual triglyceride-rich chylomicrons contacting hepatocytes resulting in fatty livers (1980). Fatty livers are seen also in Swedish medical students after an acute party. Abstinence rapidly reverses this fatty change. However, long term heavy drinking may lead to loss of fenestrae (defenestration) and blockage of the sieve. This disaster leads to high circulating lipids, milky serum, decrease in liver-vitamin A and eventually cirrhosis.

Diabetes also influences the liver sieve and so cholesterol metabolism and heart disease (2007). Viruses reaching the liver are usually smaller than 50nm to negotiate fenestrae(1978). These then may close the fenestrae, leading to cirrhosis. Other drugs such as cocaine also cause defenestration. The severe liver-toxin, dimethyl nitrosamine, in rats leads to cirrhosis in forty days and liver cancer in fifty.(1992,1996)

The liver sieve, occupying a central place in the metabolism of the body, must influence many aspects of health. Colleagues in Sydney have shown its influence in autoimmune diseases. A porous sieve facilitates the trans-endothelial hepatocyte-lymphocyte interaction. (TEHLI) where hepatocytes functioning as antigen presenting cells instruct autoimmune T lymphocytes not to attack self- proteins. This explains the deleterious inflammation resulting from smoking and rheumatoid arthritis since nicotine leads to smaller fenestrations may prevent TEHLI and autoimmune tolerance.(2006)

I predict that exercises by increasing the porosity of the liver sieve will be beneficial. These probably act by altering abdominal-thoracic pressure differentials and so hepatic blood flow.(1980) Thus are yawning, sighing and singing beneficial? Might laughter be the best medicine? May CPAP for obstructive sleep-apnoea, by counteracting deleterious abdominal pressures dilate fenestrae and so decrease strokes and heart attack by decreasing blood cholesterol? Tai chi maybe good exercise for us elderly? Abdominal obesity and belts instead of braces might be deleterious? Future genetic and epigenetic therapies are already in production and depend on a porous sieve. Dogs with haemophilia are cured by 50nm viral vectors carrying factor 9 gene through open fenestrae(2003). Alnylam,(a Boston developmental pharmaceutical company) is already testing 50nm diameter lipidoid vectors to transport inhibitory RNA via the liver sieve to hepatocytes to inhibit synthesis of rogue proteins in familial diseases such as amyloidosis and, hypercholesterolaemia (Akinc et al. 2009)

A non-invasive liver function test to measure the porosity of the Liver Sieve is urgently needed. We then may easily measures porosity needed to inhibit autoimmunity, to encourage the hepatic uptake of chylomicron-remnant cholesterol to inhibit the hepatic enzymes (HMGCoAReductase) synthesising cholesterol in "bad lipoproteins". I dream of increasing porosity of victims in septic toxic shock aiding hepatic detoxification or biliary excretion of remnant-bound endotoxins.

The good news is that, even following intense toxicity from dimethyl nitrosamine, fenestrae re-appear several days after removal of the poison However, even after cirrhosis following long term hepatitis C, the advent of anti-viral drugs may return normal liver architecture. But beware, the elderly are known to have diminished fenestrae in their liver sieves, as shown by our Sydney colleagues(2002).This decreased porosity decreases their hepatic removal of drugs. Also it may predispose to atherosclerosis, strokes and myocardial infarction. It increases diabetes by inhibiting the liver's storage of glucose as glycogen secondarily to hepatic insulin resistance from decreased porosity of the liver sieve. Might the liver sieve become more porous from the relaxation of the actin filamentous network surrounding the fenestrae in their gossamer-like sieve plates of the hepatic sinusoidal endothelium? Rafts ,the thicker regions of endothelium, may hold the answer from their pinocytotic vesicles endocytosing tiny conglomerates of proteins such as diabetic glycosylated end-products, oxy-LDL and hyperglycaemia.

We, the elderly, already trend towards decreased liver sieve porosity, and from our research perspective a sensible intermittent low dose ethanol intake is reasonable. However heavy un-remitting and defenestrating drinking would seem risky.

Thus I reiterate. "Not drinking a few days each week is excellent health advice, not only for the elderly but for younger adults as well. It is right in line with the Health Promotion Agency's low-risk weekly drinking guideline of no more than 10 standard drinks for women, 15 standard drinks for men, and at least two days of not drinking.

Here is to our Good Health!

Robin Fraser

Professor Robin Fraser

http://www.otago.ac.nz/christchurch/departments/pathology/ourpeople/otago0123071.html

Positions

Medical Director of the Canterbury Medical Research Foundation (CMRF)

Teacher of pathology and former HOD at the University of Otago, Christchurch

Retired (2013) Coroners' Pathologist

References.

Fraser,R,, Dobbs,BR, and Rogers GWT (1995).Special Article: Lipoproteins and the Liver Sieve: The Role of the Fenestrated Sinusoidal Endothelium in Lipoprotein Metabolism, Atherosclerosis, and Cirrhosis. Hepatology,21:863-874.

Fraser R, Cogger VC, Dobbs BR, Jamieson HA, Hilmer SN and LeCouteur DG (2012).The Liver Sieve and Atherosclerosis. ( invited review). Pathology,44;181-186.

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