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Wednesday, 21 August 2013

A catch-all round-up grab-bag of stuff

To start with the latest on the story of linoleic acid and cholesterol, NAFLD and NASH; this PDF
Effects of dietary cholesterol and fatty acids on plasma cholesterol level and hepatic lipoprotein metabolism
sets out what I think might be the "design flaw" in hepatic cholesterol regulation. Cholesterol is the only lipid I can think of which is produced through the TCA cycle but cannot be broken down again by beta-oxidation and the TCA cycle - it has to be conjugated and excreted. Thus the medical focus on cholesterol and disease is not, of itself, a deluded one. It is the focus on saturated fat and serum cholesterol that is 100% deluded. (Uffe Ravnskov lays out the facts about that in what should really be "enough already" style here)
As hepatic cholesterol increases, HMG-CoA reductase is downregulated to maintain homeostasis. But when intake of linoleate is high, hepatic LDL receptors are upregulated, increasing hepatic cholesterol uptake, and if dietary cholesterol is also high, perhaps HMG-CoA reductase downregulation is insufficient to cope, especially if taurine (which conjugates and removes free cholesterol) is insufficient. In the words of the paper:

There is a discrepancy in the regulation of HMG-CoA -reductase and LDL receptor activities in liver from animals fed cholesterol with linoleic acid. In spite of a high content of hepatic cholesterol and obvious suppression of hepatic HMG-CoA reductase activity, the hepatic LDL receptor activity was rather increased in animals fed cholesterol with linoleic acid in comparison with control animals (Tables 4 and 5, Fig. 1). This result suggests that fatty acids, especially linoleic acid, independently influence the regulatory pathway of LDL receptors and HMG-CoA reductase activity by cholesterol. 

The situation is further complicated by the fact that carbon from linoleic acid goes into the synthesis of other lipids - including cholesterol and palmitate. And this is consistent with another feature of NAFLD - increased rates of lipolysis and DNL, and a 2x greater flux through the TCA cycle, futile cycling which does not clear the liver of fat, but rearranges lipid carbon instead. We might hypothesise that the linoleic acid is potentially so destabilising that any excess automatically goes to make more rigid lipids, but that where there are insufficient factors to neutralise these lipids (such as taurine or CYP esterification pathways for free cholesterol, or oleic acid to promote the inclusion of palmitate in triglycerides - interesting sideline here is that high-oleic acid diets might encourage the "safe" and stable form of fatty liver), or to oxidise them (because of preoccupation with oxidising carbohydrate), they accumulate in the toxic free state. We might also observe that diets very rich in both cholesterol and linoleate are quite rare in nature, omnivores tend to substitute nuts and seeds for meat when either is less available.

But perhaps the problem does not lie with nuts and seeds at all. Perhaps, in the case of humans, who probably don't consume large amounts of soy or corn oil except in cooking, the problem is with peroxides from heated linoleate - what Bill Lagakos called "molested fats".
Finally someone has sought to answer the question of what these peroxides might do to the liver.
I don't have full-text access yet but luckily the Journal of Hepatology provides both abstract and editorial comment:

In order to test the hypothesis that peroxidized fatty acids, generated by heating of standard cooking oils, trigger hepatic inflammation, Boehm et al. performed short-term experiments in which they heated standard corn oil to raise peroxide content more than 100-fold compared to unheated oil and gavaged rats with either standard or heated corn oil for six consecutive days. The livers of animals treated with heated corn oil expressed higher levels of several inflammatory genes, including interleukin 1beta, cyclooxygenase-2 (COX-2), and tumor necrosis factor alpha. This was associated with increased infiltration of CD68 positive macrophages. Peroxidized linoleic acid induced nitric oxide synthase-1 and COX-2 in Kupffer cells and mixed non-parenchymal cells through activation of p38 MAP kinase pathway. Whether these findings are relevant to human disease remains to be determined. 

Background & Aims

Obesity and hepatic steatosis are frequently associated with the development of a non-alcoholic steatohepatitis (NASH). The mechanisms driving progression of a non-inflamed steatosis to NASH are largely unknown. Here, we investigated whether ingestion of peroxidized lipids, as being present in Western style diet, triggers the development of hepatic inflammation.


Corn oil containing peroxidized fatty acids was administered to rats by gavage for 6days. In a separate approach, hepatocytes (HC), endothelial (EC) and Kupffer cells (KC) were isolated from untreated livers, cultured, and incubated with peroxidized linoleic acid (LOOH; linoleic acid (LH) being the main fatty acid in corn oil). Samples obtained from in vivo and in vitro studies were mainly investigated by qRT-PCR and biochemical determinations of lipid peroxidation products.


Rat treatment with peroxidized corn oil resulted in increased hepatic lipid peroxidation, upregulation of nitric oxide synthetase-2 (NOS-2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα), elevation of total nitric oxides, and increase in cd68-, cd163-, TNFα-, and/or COX-2 positive immune cells in the liver. When investigating liver cell types, LOOH elevated the secretion of TNFα, p38MAPK phosphorylation, and mRNA levels of NOS-2COX-2, andTNFα, mainly in KC. The elevation of gene expression could be abrogated by inhibiting p38MAPK, which indicates that p38MAPK activation is involved in the pro-inflammatory effects of LOOH.


These data show for the first time that ingestion of peroxidized fatty acids carries a considerable pro-inflammatory stimulus into the body which reaches the liver and may trigger the development of hepatic inflammation.

edit: from the fulltext (Thanks Bill):The present data suggest that the ingestion of peroxidized linoleic acid is much more effective than the unperoxidized form in evoking pro-oxidant and pro-inflammatory processes in the liver, i.e., native linoleic acid induced shedding of TNFa from the cell surface but failed to significantly alter intracellular mRNA levels of classical pro-oxidant and pro-inflammatory genes. According to these findings, it has to be considered that increased uptake of lipid peroxidation products, as occurring with unhealthy eating habits, may contribute considerably to the generation of sparks igniting hepatic inflammation. Thus, further studies in humans are urgently required to check for a causal link between ingestion of lipid peroxides and emergence of NASH.
(Comment; knowing how significant the effect of unheated corn oil is already in animal liver inflammation models, this is some interesting news. Consider the pork-cirrhosis link again; pork is not only high in both cholesterol and linoleic acid, it needs to be eaten well-cooked)

So this allows us to construct a likely hierarchy of linoleate sources; best are nuts and seeds, next best are 11% oils like olive oil, more harmful are oils like rice bran and canola, worse still are soy, corn, sunflower and safflower oil, and worst of all? French fries and fish and chips, donuts and baked goods, and so on.

Just to prove that food quality matters in the care of chronic hepatitis C, here's a study that shows that even a low-fat diet, or a (somewhat) calorie-restricted diet, will produce some benefit in over-weight Hep C patients if food quality and exercise are put first; increased intake of olive oil, nuts, vegetables, fruit, wholegrains, increased exercise, and decreased intake of refined and processed carbohydrate, limited cholesterol and saturated fat. Which in the context of the Bulgarian diet might have meant less fried food.

Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C – a randomized trial

I think you would get these results quicker with a low-carb diet if you paid as much attention to food quality and exercise, and you would see more benefits in terms of quality of life and extrahepatic syndromes, but the important thing is that food quality trumps all, and even makes calorie restriction and fat restriction tolerable (if it was as great as reported).
File:Rhodope Mountains Bulgarian food 04.JPG

Lastly, a long-overdue link to It'sthewooo's probiotic series. Part 1 Part 2 Part 3 I recommend taking probiotics, but I haven't gone into the details much because I see it as something of a personal quest and complicated. Reading someone else's honest description of their findings is a good way to prepare yourself, or compare your results, and Woo is the model of a reliable guide here. And generally a most interesting and entertaining blogger. Someone faulted Woo for not providing many references for her claims, I considered this, and actually couldn't remember a time when she'd been wrong about some statement of medical nous. People can and should do their own research, links are a courtesy, when you're say, a nurse like Woo, and have to know stuff because you've been taught it, and see the truth of it every day, pulling up references for everything is a little infra dig.
If I don't give a link for everything, look it up yourself and prove me wrong. And where I do give a reference, that may be mistaken anyway, or misinterpreted by me, so people who really want to engage with the science, should develop the habit of questioning it. Anyone worth listening to and still engaged in learning is modifying their opinion all the time.


ItsTheWooo said...

Another benefit to emphasizing food quality for hep c is that micronutrients and overall health relates to immunity and ability to resist viral syndromes; other than the benefits of better quality fats with regard to potential hepatic complications you have the factor of preventing viral replication in the first place by , say, eating healthful foods and being replete of nutrients like vitamin D3.

My writing is largely unreferenced I know, will never be a professional blogger but if one fact checks/verifies my arguments you shall find nary a quackery...and if so, I apologize ;)

These days I have almost zero signs of any digestive / gastric upset. So amazing! Quality of life way better! Not sure how much is owed to D3 too but still using probiotic and do not intend to stop.

George Henderson said...

Yes, there's some evidence that HBV is less likely to become chronic in persons with adequate selenium status, and optimal selenium protects against hepatocellular cancer.
I figure that the drop in liver enzymes in the Bucharest study could be entirely due to the extra antioxidants in the diet. These enzyme scores were not very high to begin with. And WHY is this called a Liver Function Test? GGT, AST, ALT are hepatocyte damage measurements that say NOTHING about liver function. If anything, they indicate the influence of a likely threat to liver function at some indeterminate future date.
Bilirubin, albumin, platelets, and whether triglycerides are diet-appropriate - those are markers of liver FUNCTION.

Qualified people - R D Feinman, for example - and people who think they are qualified, like Carbsane, don't supply link references. I might stop doing it except for novelties, and of course music. Googling stuff oneself is easy and satisfying and anyone can learn to do it.

Charles Grashow said...

On Dr Briffa's blog you said "I have never seen anyone who feels better on statins. People tend to be breathless and tired, if they do not develop gut and muscle problems. I’m opposed to taking any drug that doesn’t make you happier and healthier than you were before you started. Diarrhea and ulcerative colitis are statin side effects that are under-reported because attributed to other causes, whereas myositis is unusual in other contexts so easier to diagnose. And then there are the neurological syndromes.
In theory one could get the same benefits by supplementing taurine, magnesium and fish oil, or by restricting dietary cholesterol, refined carbohydrate and omega-6 oils."

Have you considered that people may be taking the wrong statin?

For example - 3 of the statins currently available are made via fermentation from mold - if one has an allergy to mold that would cause problems.

There are also genetics involved.

Three SLCO1B1 genotypes have been identified and classified in terms of their effect on statin metabolism in the liver—normal (T/T), heterozygote (T/C), and homozygote (C/C):
The T/T genotype (valine/valine) is classified as normal. These patients have a normal ability to metabolize statins (about 70% of the population). Standard doses of statins are recommended for LDL-C lowering and CVD risk reduction.
The T/C genotype (valine/alanine) is classified as an intermediate metabolizer. These patients have a decreased ability to metabolize statins (about 26% of the population). They are at a four-fold increased risk for developing statin induced myopathy. They also achieve less LDL-C lowering from the statin that they receive.
The C/C genotype (alanine/alanine) is classified as a poor metabolizer. These patients have a significantly decreased ability to metabolize statins (up to 5% of the population). They are at a seventeen-fold increased risk of developing myopathy on statin therapy.

Charles Grashow said...

Then there is the question of whether one is a high producer/absorber of cholesterol - markers of cholesterol production (lathosterol and desmosterol) and absorption (beta-sitosterol, campesterol, and cholestanol).

Cholesterol synthesis/absorption status was not markedly altered by diet, but the decrease in plasma LDL-C due to the Mediterranean-type diet occurred only in low absorbers of cholesterol. This should be considered during further dietary interventions.

These data suggest that impaired cholesterol homeostasis, reflected by lower synthesis and higher absorption marker concentrations, are highly significant independent predictors of prevalent CVD in this study population.
SO - it's not as cut and dried as one would rthink.

Charles Grashow said...

We provide compelling evidence that at least one common variant in the SLCO1B1 gene substantially alters the risk of simvastatin-induced myopathy. Among patients taking 20 to 40 mg of simvastatin daily (or standard doses of other statins), the incidence of myopathy is typically only about 1 per 10,000 patients per year,4 and the effect of these gene variants on the absolute risk of myopathy is likely to be small (as indicated by our results among participants in the Heart Protection Study). In contrast, the risk of myopathy may be substantially increased in patients who take 80 mg of simvastatin daily (and some other high-dose statin regimens), as well as in those who are also receiving certain other drugs2-4 (e.g., cyclosporine and, as we found in SEARCH, amiodarone11). Hence, the use of those drugs in subjects who are taking such high doses of statins and who have the C allele of the rs4149056 polymorphism may produce particularly high risks of myopathy (Figure 2).

George Henderson said...

Thanks Charles, interesting stuff. I would be very surprised if ANY doctor prescribing statins in NZ runs genetic testing to determine safety of what they are doing. This is telling us that safe use of statins, if such a thing exists, is a prerogative of the very rich.
Many things we use are produced by fermentation and I would expect that allergic reactions are rare.
If statins promote health, then statin users should be fitter and happier than they are. Subjective effects, QOL, are important factors. I think these minor side-effects, breathlessness, diarrhea, forgetfulness, are sub-clinical manifestations of the same processes that cause more lethal side-effects.
Thanks for the links. If statins are prescribed on the basis of total C levels, and these are misleading guides to cholesterol synthesis and CVD risks, then it is little wonder the benefits in general use are so nugatory.

Charles Grashow said...

My insurance (in the USA) covers these tests - I should be getting them next month when I see my doctor. If I get them I will let you know the results.

George Henderson said...

Interesting link from Peter D about omega-6 EFAs fueling cancer growth - specifically hepatoma.

Perfusion of tumors with normolipemic blood containing added linoleic and arachidonic acids increased [3H]thymidine incorporation. Blood mixtures containing palmitic, stearic, and oleic acids were inactive.

The whole of Peter's discussion is here:

Joakim said...
This comment has been removed by a blog administrator.
Joakim said...

Great blog Mr Henderson! I have a rare scalp/hair disorder by the name Lichen planopilrais(lichen planus on the scalp) and the latest pub med research linking my disorder to changes in the cholesterol biosynthetic pathway in the skin.

Do you think there is a connection with my body not able to take up cholesterol and by so the cholesterol pathway changes in my skin?

I can add that I also have serious digestive problems and lsot 9kg in 2 months.

George Henderson said...

That's very interesting and may have implications for Hep C where chlesterol completion is also being blocked.
At first sight this looks like something that probiotics might help, because of the TLR and interferon connection. There is probably a connection between what's happening with the gut and with the skin. There are reports of improving LP with gluten-free and paleo diets. Have a look at this example

I had mild psoriasis clear up when I supplemented selenium, zinc, and fish oil. Not the same thing, but the oils and antioxidants in the skin will be important, and the gut; I would probably try a rhamnosus plus bifidus probiotic, and maybe aloe vera juice, or spirulina, but I'd add spirulina separately just in case, but these are the things that helped my gut most. And vitamin D3.
That and a low-carb diet without grains, legumes, sugar and vege seed oils.
You don't say if you've tried any supplements or eat any special way.

Generally the best advice about the gut is in Chris Kresser's Healthy Skeptic blog. He has an entry on the gut-skin axis here:

George Henderson said...

P.S. the precursor they used to create inflammation in the paper, 7-DHC, is converted to vitamin D3 under UVB light. Do you get much sun, and what happens when you do? It may be that your skin is trying to make vitamin D but not getting enough sun.

George Henderson said...

I found this:
It has been suggested that infection with hepatitis C virus may be associated with the development of lichen planus and that geographical area may be an important factor affecting the relative risk.

but not in NW England.
Is this because in colder regions, the effect of vit D deficiency is more important than any HCV association?

George Henderson said...

See figure 3 here - secondary bile acids prevent atherosclerosis?