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)
Anyway:
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.
Methods
Corn oil containing peroxidized fatty acids was administered to rats by gavage for 6
days. 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.
days. 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.Results
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-2, COX-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.
Conclusions
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).
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.
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.
