From this paper: "Hepatic cholesterol accumulation is driven by a deeply deranged cellular cholesterol homeostasis, characterized by elevated cholesterol synthesis and uptake from circulating lipoproteins and by a reduced cholesterol excretion."
This is what happens when simple fatty liver becomes NASH, with progression of fibrosis and cirrhosis.
I commented at the time "elevated cholesterol synthesis = high PUFA diet lowering serum cholesterol and upregulating LDL receptors (lower serum cholesterol= more intracellular cholesterol), also excess sugars > TG especially with choline deficiency.
Reduced cholesterol excretion = low esterification due to deficiency of taurine, glycine, also Mg+, esp. with choline deficiency."
The first part of that is based on the mechanical function of cholesterol as a membrane-stabilising agent . Extra PUFA in cell membranes demands extra cholesterol be produced by, and much retained by, the liver. Serum cholesterol may go down (the supposed "good" result), but the NASH example shows that serum cholesterol readings are in fact a very weak and misleading indicator of intracellular disease processes involving cholesterol.
You can have "low cholesterol" while accumulating cholesterol is killing you in a much more sure and certain way than via any "lipid hypothesis" mechanism, and this might also apply to cells outside the liver in the presence of fatty liver disease.
(ew - soy oil)
The excellent Suppversity blog yesterday analysed a recent paper that shows this happening with regard to the feeding of soy oil to Wistar rats.
http://suppversity.blogspot.co.nz/2013/08/high-fish-soy-lard-low-fat-diets-how-do.html
http://suppversity.blogspot.co.nz/2013/08/high-fish-soy-lard-low-fat-diets-how-do.html
Compared to lard-fed rats, or low-fat rats, the soy oil-fed rats had slightly lower serum cholesterol. As we tend to see in humans. But hepatic cholesterol was doubled (even though lard is a source of dietary cholesterol, and soy oil isn't). Hepatic NEFA (non-esterified fatty acids) were also doubled. This is a sure sign of trouble, more so than the elevated liver triglycerides. 
(Picture borrowed from Suppversity blog and based on Hashimoto et al. 2013)
The other interesting thing was the generally beneficial picture seen with fish-oil feeding. Combined with alcohol, fish oil is deadly to the liver. Granted the fish oil effects were extreme, reflecting the enormous dosage, and perhaps undesirable in other ways, such as depressed immunity, but fish oil wasn't causing fatty liver or predisposing to NASH in this model.
It's all about omega 6. And, I suspect, about linoleate, not arachidonic acid.
This was 45% energy from soy oil, which (edit) was about 50% linoleate (a bottle I saw today was 58% PUFA). If your hepatic cholesterol is increased, and you also eat foods high in cholesterol, the liver isn't going to cope with that extra cholesterol, is it? It's already struggling with its own production.
So the very "food" you consume to help with your imagined cholesterol problem can be causing a very real and lethal cholesterol problem. Unless that food is fish. Or nuts, for a different, complicated and somewhat obscure reason, probably not much to do with linoleate.
(Picture borrowed from Suppversity blog and based on Hashimoto et al. 2013)
The other interesting thing was the generally beneficial picture seen with fish-oil feeding. Combined with alcohol, fish oil is deadly to the liver. Granted the fish oil effects were extreme, reflecting the enormous dosage, and perhaps undesirable in other ways, such as depressed immunity, but fish oil wasn't causing fatty liver or predisposing to NASH in this model.
It's all about omega 6. And, I suspect, about linoleate, not arachidonic acid.
This was 45% energy from soy oil, which (edit) was about 50% linoleate (a bottle I saw today was 58% PUFA). If your hepatic cholesterol is increased, and you also eat foods high in cholesterol, the liver isn't going to cope with that extra cholesterol, is it? It's already struggling with its own production.
So the very "food" you consume to help with your imagined cholesterol problem can be causing a very real and lethal cholesterol problem. Unless that food is fish. Or nuts, for a different, complicated and somewhat obscure reason, probably not much to do with linoleate.
10 comments:
Soy alone won’t cause NASH in rodents, especially in the exceptionally fibrosis-resistant C57’s. They really need methionine and/or choline restriction, which seems to support your point that increased cholesterol synthesis and/or uptake must be accompanied by impaired cholesterol export.
Non sequiter: agreed also about the fish oils. Comined with any other insults = detrimental (eg, alcohol); but alone, they are probably beneficial – patients undergoing TPN with Intralipid (soybean oil) are at much greater risk of liver damage than those who are lucky enough to qualify for something like Omegaven which is high in fish oils.
That's right, it's a set-up for some other factor to wander in and take the liver down. Dietary cholesterol maybe, but human intakes don't match the 2% (by weight I presume) that's toxic to these rats.
In humans with HCV (which deranges cholesterol homeostasis in its own right), fatty liver is associated with cirrhosis OR 5.0 or thereabouts. And PUFA correlates with steatosis at OR 2.7 or 2.9 if memory serves.
The fish oil for NAFLD paper I linked to a while ago looked really encouraging for a review of a supplement intervention. Especially a PUFA supplement in a liver disease.
Fish oil TPN I believe is also safer because much less of it is needed. The EFAs are plainly more "essential" than those in soy.
I wonder if this omega-6 effect, whatever else it does, promotes diabetes. All those NEFAs, and of course the LA swamping the DHA signal. Maybe the protective role of dairy fat in DM2 is related to what displaces dairy fat in the diet.
Wow 2%. That'd be about 10 grams per 2000 kcal.
Probably impossible for a human: 83 eggs = 2000 kcal = 6 grams cholesterol... which leads me to think maybe that "other factor," especially in rodent diets, is oxidized cholesterol. There's probably some naturally occuring non-oxidized cholesterol, but to get 2% would definitely require adding straight cholesterol.
In the cholesterol accumulation papers, it seems accumulation promotes oxidation. There is a to-and-fro between oxidation of cholesterol and cardiolipin that affects the mito membrane.
And of course the high PUFA levels will make oxidation more likely.
And vitamin E has some benefit in NASH, some people responding better than others. http://www.nejm.org/doi/full/10.1056/NEJMoa0907929
this was a comparison with the anti-diabetic drug pioglitazone.
The soy oil used in the Hashimito experiment was higher in n-6 than I thought: nearly 50pc. So over 20pc energy as n-6.
High hepatic cholesterol and NEFAs seems to me like a house of cards, ready for any toxic or immunological trigger to precipitate a less easily reversible pathology.
From the first link in the post:
hepatic triglyceride (Tg) accumulation is not per se toxic, but rather protects the liver by buffering the accumulation of lipotoxic Tg precursors. Consistent with this view, subjects who are able to store excessive fat as neutral cholesterol esters and TG develop steatosis but not NASH and may be considered “good fat storers”, while subjects who are unable to synthesize neutral lipids accumulate toxic lipid species and develop progressive inflammation and fibrosis, leading to NASH.
High linoleic acid intakes = poor fat storage. Oleic acid probably promotes healthier hepatic fat storage.
Goji berry is a source of taurine:
http://www.ncbi.nlm.nih.gov/pubmed/21820420
This berry has a hepatoprotective polysacharride effective at normal dietary intakes. Generally I don't believe in superfoods, but Goji seems medicinal for the liver and is used in a modern TCM liver tonic (a mix of goji, and rosa rugosa petal, which contains tellimagrandin 1, an HCV invasion inhibitor).
http://www.ncbi.nlm.nih.gov/pubmed/20144544
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.
http://www.jlr.org/content/31/8/1413.full.pdf
Another good post, George. This following link had a bit of an ANZAC feel to it, so thought I'd share:
http://gameauland.com/that-sugar-film-teaser/
Of course there appears to be some obvious flaws in it, but I guess it has promise.
It looks interesting, especially if it brings in fat, cholesterol and so on. Should improve sales of aspartame.
In HCV epidemiology (such as it is) fructose has only weak association with fibrosis (OR 1.147) dwarfed by effect of PUFA (OR 2.7 steatosis - alcohol is only 2.4!) and total carbohydrate (OR 2.9 fibrosis).
But science is weak, only uses high/low differential where quartiles or quintiles would give much more clarity.
To be exact, most HCV plus diet epidemiology papers seem to use a formula like this; comparing persons with intake (total or calories %) below or at the RDI for any given macronutrient against persons with intake above the RDI.
This kind of assumes that the RDI is set at the level most relevant for its effects on hep C...
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