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Tuesday, 13 November 2012

HCV replication; diabetes, main roads, railways, and tanks.

Back to the raison d'etre for this blog; the supposition that HCV replication can be restricted, and the symptoms mitigated, by following a carbohydrate-restricted, low-PUFA, high SFA diet.

Another way of looking at this is, genomically. HCV promotes certain genes that it finds helpful, and manipulates others;

HCV promotes -
FOX01 - this transcription factor increases the production of glucose, which, amongst other things, inhibits PPAR-alpha, a gene that is unfriendly to HCV. FOX01 is also activated by fructose.
DGAT1 - this protein synthesizes triglycerides from dietary fats and carbohydrates. It is also stimulated by glucose and fructose - dietary carbohydrate. The tryglcerides are released as VLDL, which the HCV virion accompanies.
HMG-CoA reductase. This protein synthesizes a geranylgeranyl group which HCV needs to activate another gene. The end product should be cholesterol, but HCV disrupts cholesterol completion in order to keep the protein working. Dietary cholesterol inhibits HMG-CoA reductase.
LDL-cholesterol receptor complex (LDL-R) - an array of proteins that HCV virion uses to infect liver cells. HCV promotes LDL-R indirectly by restricting hepatic cholesterol production. A diet high in PUFA (seed oils) promotes LDL-R, a diet high in saturated fat reduces LDL-R expression.

PPAR-alpha: this gene inhibits DGAT1 and HCV replication. This is the basis for the HCV inhibiting effect of the grapefruit flavanone naringenin. PPAR-alpha is activated by fasting, calorie restriction, and carbohydrate restriction, as well as the omega-3 fatty acid DHA and naringenin. It is the fat-burning gene, pretty much; it inhibits the conversion of free fatty acids (fuel form) to triglycerides (storage form).

The presence of an active HCV infection can be metabolically disruptive, leading to type 2 diabetes and fatty liver. This review shows the link between low cholesterol and diabetes:
http://beforeitsnews.com/healthcare/2012/11/hepatitis-c-virus-infection-and-diabetes-not-a-straightforward-relationship-2443048.html

 In a meta-analysis of 34 studies, HCV infection was found to increase the risk of diabetes in both retrospective (adjusted odds ratio 1.68, 95% CI 1.15–2.20) and prospective studies (adjusted hazard ratio 1.67, 95% CI 1.28–2.06).[1] Furthermore, patients with HCV infection have higher risk of diabetes than patients with hepatitis B virus (HBV) infection.
By multivariate analysis, HCV infection was independently associated with diabetes only in subjects without hyperlipidemia (defined as triglycerides above 150 mg/dL and/or total cholesterol above 200 mg/dL; adjusted odds ratio 1.35, 95% CI 1.17–1.55) but not in those with hyperlipidemia. 

Interestingly, high triglycerides were inversely associated with diabetes (but note that this was either/or - it was not necessary to have both cholesterol over 200 and TG over 150 for protection). This can be explained in a number of ways; high TG is a sign of insulin sensitivity on the usual high-carbohydrate diet; it shows that the liver is responding to the diet naturally; that blood sugar is being kept low by lipid synthesis.

This is matched by the surprising finding that low HDL is associated with SVR (sustained viral clearance after antiviral treatment). http://www.ncbi.nlm.nih.gov/pubmed/20568303

In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001).

If low HDL is the usual response to the usual diet, it may be just a sign of liver function and low viral titres.
I suggest that higher TG and lower HDL are not important signs unless you choose to eat a diet that should promote these anyway; in which case they are signs of normality, if not of health.

Serum TG may be lowered by HCV because cholesterol production is low; in this case, the TGs will have trouble being packaged and exported, and fatty liver will result (similar to what happens when choline, also required for triglyceride export, is restricted).
Despite HCV depending on TG and VLDL cholesterol, this benefits the virus, because low levels of lipids and cholesterol see a bigger effort from cells to take in the amounts present (more LDL-R). With fewer lipid particles in the blood, and more LDL-R, the LDL-R are more available to bind to the HCV virions.
(Technically, this refers to some parts of the LDL-receptor complex like the friendly-sounding protein Niemann-Pick C1 like 1:
 
http://www.ncbi.nlm.nih.gov/pubmed/22231557 )


Can HCV, justly famous for its high rate of mutation, often one step ahead of your antibodies, mutate to use different receptors? Certainly, with regard to the LDL-R complex proteins required there seem to be variations among the samples studied. It is possible that HCV quasispecies could arise that can leave infected cells without VLDL exocytosis and enter without the LDL-R. But highly variant quasispecies are not very viable. Lipid transport is the "main road" that HCV exploits. There is a lot of traffic down that way. Taking another route would see the virus marginalized and struggling to survive.

Consider the metaphor of the tank.

Tanks are all-terrain vehicles - they can travel where cars and trucks cannot. Yet most tank campaigns in history have been battles for control of the roads and railways, which allow faster deployment of larger numbers of tanks.


The lipid transport system is to HCV what this railway is to the tanks. Higher cholesterol and LDL counts represent more empty trains. Lower counts represent empty stations with lots of helpers ready to unload the trains, trains that are more likely to be carrying tanks.


The ideal cholesterol level is over 200, but probably not that much over (220-240 seems to be about right). Lipids, like blood glucose, are a form of energy and therefore a response to how much we eat as well as the type of foods we eat; it may also be that the people with the high-TG, low-HDL, high cholesterol picture were eating more and therefore tended to have better immunity than other patients who were off their food, perhaps due to poverty, food allergies, or anorexia. You can alter lipid counts by eating more or less food, as well as by changing the kinds of food you eat.

While I think ketogenic dieting - for short periods - or intermittent fasting, which should generate intermittent ketosis - is a powerful tool against HCV, there is one dissenting voice:
Paul Jaminet has written "Ketogenic diets, which starve the brain of glucose but feed it with small molecules derived from fats, are highly effective against bacterial infections of the central nervous system, since bacteria depend on glucose metabolism. But hepatitis B and C viruses can utilize the process of gluconeogenesis—manufacture of glucose from protein—for their own benefit, so people with hepatitis benefit from higher carb diets." 
http://www.psychologytoday.com/blog/perfect-health-diet/201201/is-there-perfect-diet
Firstly, by higher carb Paul doesn't necessarily mean food-pyramid high. About 50-75g carb per day is enough to suppress ketosis and gluconeogenesis (this is about the amount I usually eat). He is probably right that this will result in lower blood glucose and more metabolic flexibility in some people with HCV than following a ketogenic diet. Paul also recommends restriction of fructose and PUFA, and intermittent fasting, in general terms (the line about gluconeogenesis seems to be his only specific HCV reference).
However, the FOX01 activation, though important to HCV, is only part of its arsenal. We also need to consider the DAGT1, which will be highly suppressed on a ketogenic diet (which is where PPAR-alpha becomes most active). And, paradoxically, FOX01 can be suppressed by deep ketosis (presumably when ketone bodies are produced in amounts that begin to reduce the brain's requirement for glucose).

The compromise that I find comfortable is to eat a little "safe starch" carbohydrate once a day, plus a piece of fruit, and fast intermittently (as described in "Dining in the Fourth Dimension"). My viral load was lowest in ketosis, but it is not much higher now and I am even more comfortable.

Butter at War

This is my new favourite blog: http://nelliebswartimerationing.blogspot.co.nz/2012/11/butter-rationing-in-new-zealand.html

A family living on New Zealand wartime rations.
Some silly people say that wartime rationing produced healthier people, not because cigarettes, alcohol, and sweets were harder to get, but because less saturated fat was being eaten.

Let's see, shall we?

The following information was issued by the Department of Health, Wellington, New Zealand, in 1943.

Butter Rationing

Compensating Foods Suggested.

With the introduction of butter rationing, it is important that people should know the foods that can help to compensate for the loss of food value normally supplied by the quantities of butter to which they have become accustomed.

In the first place, butter is butterfat, and the two other foods which contain butterfat are milk and cheese.
The amount of milk normally required daily is :


Two glasses for Adults
Three to Four glasses for Children.

With less butter available it is necessary that all of this milk - and more, if possible - should be used.
The top creamy milk should be saved for the children's porridge and puddings.

More cheese should be used.
Grate it in salads, eat it in chunks with bread and a little of your butter, or cook it for the evening meal.

An important constituent of butter is Vitamin A, which enables the body to resist infection, and also helps to avoid the condition known as night-blindness.
Vitamin A is present, for example, in eggs and liver.
Cheese, eggs, and liver are all foods which can form part of the tea meal - the meal at which so much butter was eaten.

The green and yellow vegetables - leafy vegetables, carrots, kumeras (NZ sweet potato) - can all help in providing Vitamin A.  So can tomatoes.

To replace the Vitamin A, then, use milk, cheese, eggs, liver, green and yellow vegetables and tomatoes.

For baking purposes dripping clarified at home may be used, and if the butter for spreading runs out, salted beef dripping in which an onion has been cooked, is suggested as a substitute.

To sum up, the following foods will help to make up the deficiency caused by butter restrictions :


1.  milk and cheese
2.  eggs and liver
3.  green and yellow vegetables and tomatoes
4.  salted beef dripping for spreading on bread
5.  clarified dripping for baking.





- My God, governments knew more about nutrition then than they do now!



As in this Disney WW2 nutrition film:



The opening up of the slippery downward slopes in New Zealand governmental nutritional policy dates from 1974:

"Margarine could not be sold to the public from 1908 until 1974. To get it before 1974, you needed a doctor's prescription. When the ban was ended, the dairy industry asked for another concession -- that Margarine manufacturers be forced to colour it blue. This time, Parliament told them to get stuffed. The gravy train for them had ended." 


16 comments:

artee03 said...

A balanced diet rich in unadulterated foods alleviates many ailments of the modern world

honora said...

That's another change. The government panders to the dairy industry big time now!

George Henderson said...

Unfortunately milk in N.Z. is now a of processed food, and the drive is to export it for cash.
Nourishing the people of the country is no longer seen as a desirable political goal - they might get fat!

Paul N said...

Amazing video!

It is interesting to note the differences compared to todays "five food groups".
There is no wheat/bread mentioned, and there are *no* "oils"

I can easily see how eating to those three groups would do fine, and it is actually fairly close to Paul Jaminet's Perfect Health diet, though he would question some of the grains.


Also, a family that was farming to produce those three groups would be pretty sustainable - minimal inputs if fuel, fertiliser and pesticides.

Unlike today's monoculture farms...

George Henderson said...

In British goverment films of the 30s there are also 3 groups;
energy foods (fats, sugar and starches)
building foods (protein - meat, milk, eggs, beans)
protective foods (vitamins; foods high in vitamin A and D such as liver, butter, also vegetables and fruit)
Some overlap, but the 3 functions of nutrition were well described.

These guys are my heroes today:
http://www.facebook.com/NativeDiet

thewheatgrassboy said...
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thewheatgrassboy said...
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thewheatgrassboy said...

Your article is very intresting .I have found that same strategies help also with HIV

George Henderson said...

Selenium is equally important in both infections, it is sequestered by both viruses in much the same way.

http://jid.oxfordjournals.org/content/182/Supplement_1/S69.long

thewheatgrassboy said...

Yes definately ..Have you searched the role of glutathione ?

I was very low carb for years and it served me well but a year ago i developed some issues that seem to go away when i add some safe starches but not more than 300 calories from them ..i think Paul may be right..

Paul N said...

I think Ayurveda had three food groups too.

Interesting that they are all based on the food function, rather than the food "type" - as are the modern food groups.

I read somewhere a pretty good simplified summary of the paleo diet - healthy proteins (i.e. no grains/legumes) for building, healthy (saturated) fats for energy, and coloured vegetables/fruits for "health".

Sounds pretty similar to the Terry Wahls diet.

Interesting link to the Native diet. I wish those guys well. A big part of native cultures is honouring their ancestors, and honouring their ancestral food fits in with that philosophy.

More sustainable too...

George Henderson said...

@ Paul, absolutely; the tikanga of the native diet is an important part of it. And Weston A. Price are right to give traditions equal weight with science; metabolism is more than a chemistry class. Recipe books are a fusion of tradition and experiment.

@ wheatgrass, I agree; I think it's sometimes necessary to go through VLC to straighten out the gut flora and heal the nerves, but it's not always optimal to stay there. Returning briefly now and then for a reboot works for me now. About 300cal would be right. Going VLC does seem to lower the requirement for carbohydrate long-term.

George Henderson said...
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George Henderson said...

this just in - DHA oxidation activates PPAR-alpha.
You need fish oil plus an antioxidant to get this effect; Fish oil plus vit E, or krill oil.

"Of all the PUFAs, DHA is the most susceptible to spontaneous oxidation, due to its chemical structure. To date, such nonenzymatic oxidation pathways and their products have been largely ignored by investigators, partly due to the suspicion that the rate of nonenzymatic n-3 PUFA oxidation in vivo is negligible. Also, because the dogma regarding lipid peroxides has always been that they are toxic and undesirable, the possibility that they may be involved in mediating the beneficial effect of n-3 PUFAs is counterintuitive.

But accumulating evidence suggests that spontaneously oxidized PUFAs can be beneficial in many contexts, due largely to the fact that they are highly reactive agonists for certain receptors. For example, recent reports demonstrate that oxidized DHA has a high affinity for the peroxisome proliferator-activated receptor (PPAR) family of transcription factors, which regulate cellular differentiation, development, metabolism, and tumorigenesis. Moreover, oxidized DHA has a greater PPAR-activating effect than any other PPAR ligand tested."
http://www.the-scientist.com/?articles.view/articleNo/32901/title/Omega-3s--Fishing-for-a-Mechanism/

Hyperlipid, of course, has an old post about this: http://high-fat-nutrition.blogspot.co.nz/2008/08/age-rage-and-ale-vldl-degradation.html

Read all the AGE, RAGE and ALE posts and links to get the full picture.

DHA is an approved PUFA in the high-fat hep C diet.

Paul N said...

I have read numerously about what happens when PUFA is taken in isolation, without the naturally accompanying anti-oxidants.

Vit E and C seems to be particularly good.
I use red palm oil for my vit E, as it has the tocotrienol form - great stuff.

I have found taking flax +palm oil has significantly reduced gum inflammation, as Seth Roberts and others have found.

George Henderson said...

They sell palm oil here in the Arab shops, as "vegetable ghee"; I might give it a try.
when I switched from rice bran oil to dripping, my skin stopped burning easily. Previously, vitamin E was the only treatment for this, but I no longer required it to prevent blisters. This was a good illustration of the vitamin E sparing action of saturated fat plus PUFA restriction. It's probably no coincidence that fire-walking is a pastime of coconut-eating peoples.