So what gives? What is the nature of the interaction between PUFAs and other dietary components or metabolic states that produces inflammation?
In an earlier blog post I identified the enzyme systems upregulated in NAFLD as those of the microsomal ethanol oxidase system (MEOS) and also showed that the evolutionary function of the MEOS is to degrade PUFA, rather than alcohol which is a latecomer to our diets.
But what activates the MEOS when alcohol does not? How, for example, does fructose send PUFAs down this pathway, and how does this promote inflammation?
I found a clue in this hepatitis C editorial by Jenny Heathcote on a study in which weight loss improved liver function. This is some quite brilliant speculation.
Here is the description of fatty liver due to insulin resistance (HCV causes IR by a pharmacological action of its core protein):
In peripheral tissues, insulin normally downregulates the hormone sensitive lipase (HSL) enzyme responsible for hydrolysis of stored triglycerides from free fatty acids within adipocytes. In patients who are insulin resistant, this enzyme is no longer suppressed. In addition, counterregulatory hormones such as catecholamines, glucagon, and growth hormone are increased in response to increased circulating insulin levels. These counterregulatory hormones stimulate HSL to hydrolyse more triglycerides into free fatty acids, the end result being an increased flux of dietary and stored free fatty acids away from the adipose tissues and towards the liver. Unfortunately, Hickman et al did not measure free fatty acid levels before or after the weight reduction programme. Within the liver, insulin upregulates esterification of free fatty acids to triglycerides. Once the triglycerides are formed, insulin downregulates the secretory pathways, thus favouring increased storage of triglycerides in the cytosolic pool. Furthermore, free fatty acids can themselves upregulate the esterification pathway. The net result is a positive feedback cycle contributing to an ever increasing amount of free fatty acids and triglycerides in the liver. Thus portal hyperinsulinaemia leads to hepatic steatosis.
And here is the description of how hepatic steatosis influences PUFA disposal:
These studies have suggested that the presence of fat in patients with hepatitis C is associated with markers of progressive liver disease in that fat was associated with increased stellate cell activation, but the mechanism by which this takes place is uncertain. It is possible that this occurs secondary to saturation of beta oxidation pathways within mitochondria which then leads to free fatty acids becoming more available to intracellular microsomes where they undergo lipid peroxidation. There are three main products of microsomal lipid peroxidation: malondialdehyde, 4-hydroxynonenal, and hydrogen peroxide. Malondialdehyde has been shown to activate stellate cells to produce fibrin, and may be responsible at least in part for liver fibrosis in patients with non-alcoholic steatohepatitis.
Malondialdehyde (MDA) and 4-HNE are unsaturated products of PUFA, and H2O2 is also a step in the MEOS disposal of PUFA, requiring catalase for its reduction to H2O + O.
We can see how this relates to the "essential" role that PUFA plays in the development of alcoholic liver disease; not only can the liver become fatty from the conversion of alcohol to triglycerides, but also the disposal of excess ethanol through the MEOS has upregulated this enzyme system (hepatic CYP2E1 is upregulated 10-fold by ethanol); to add insult to injury, the liver's ability to dispose of excess fat via beta oxidation is impaired by the depletion of NAD+ during the conversion of ethanol to fat.
But another clue was supplied by Tucker Goodrich, the PUFA ninja, who found a rodent study showing that 4-HNE and 9-ONE could themselves be cleared if beta-oxidation pathways were upregulated enough, that is, by a ketogenic diet.
Our results showed that livers from rats fed ketogenic diet or high fat mix diet had high ω-6 polyunsaturated fatty acid concentrations and markers of oxidative stress. However, high concentrations of HNE (1.6 ± 0.5 nmol/g) and ONE (0.9 ± 0.2 nmol/g) were only found in livers from rats fed the high fat mix diet. Livers from rats fed the ketogenic diet had low HNE (0.8 ± 0.1 nmol/g) and ONE (0.4 ± 0.07 nmol/g), similar to rats fed the standard diet. A possible explanation is that the predominant pathway of HNE catabolism (i.e. beta oxidation) is activated in the liver by the ketogenic diet. This is consistent with a 10 fold decrease in malonyl-CoA in livers from rats fed a ketogenic diet compared to a standard diet. The accelerated catabolism of HNE lowers HNE and HNE analog concentrations in livers from rats fed the ketogenic diet. On the other hand, rats fed the high fat mix diet had high rates of lipid synthesis and low rates of fatty acid oxidation, resulting in the slowing down of the catabolic disposal of HNE and HNE analogs. Thus, decreased HNE catabolism by a high fat mix diet induces high concentrations of HNE and HNE analogs. The results of the present work suggested a potential causal relationship to metabolic syndrome induced by western diets (i.e. high fat mix), as well as the effects of the ketogenic diet on the catabolism of lipid peroxidation products in liver.
So - any state in which beta-oxidation is inhibited, but fat is present, will see PUFA shunted into the microsome - essentially the MEOS - and a high production of damaging peroxides and aldehydes. This also happens when mice are fed a ketogenic diet, but the aldehydes can be disposed of by beta-oxidation.
Note that the high fat (non-keto) diet in the mouse study was the Surwit diet relatively low in PUFA and MUFA (coconut and soy oil), overloading beta-oxidation with a mixture of ~50% saturated fat and 22.5% sucrose. Don't try this at home, kids.
For reasons of time I haven't gone into every possible ramification such as the role of peroxisomal oxidation in PUFA disposal, the proper function of the MEOS (making and disposing of eicosanoids), the hormetic effect on antioxidant systems of low level HNE production, and the difference between liver and other fat-burning tissues (i.e. is this relevant to heart disease if the same thing happens in muscle, macrophages, or endothelial cells? Magic 8 ball says very probably).
However, here's a model that allows us to predict and explain the likely role of PUFA in inflammatory diseases at a metabolic level. Especially, for now, liver diseases.
* FFQ epidemiology studies are notoriously inaccurate at capturing intakes of calories (and protein, which often looks wonky in epidemiology). They really can't tell you in what context PUFA is being consumed, and in any case it's hard to see how deep frying oil in food can really be measured - do you even know what your chips (fries) are cooked in and in what part of the FFQ would you put this information?
Structural and Functional Changes in Human Insulin Induced by the Lipid Peroxidation Byproducts 4-Hydroxy-2-nonenal and 4-Hydroxy-2-hexenal
 Browning JD, Baker JA, Rogers T et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011 May; 93(5): 1048–1052.
 Heathcote J. Weighty issues in hepatitis C. Gut. 2002;51(1):7-8.
 Li Q, Tomcik K, Zhang S, Puchowicz MA, Zhang G-F. Dietary-regulation of catabolic disposal of 4-hydroxynonenal analogs in rat liver. Free radical biology & medicine. 2012;52(6):1043-1053. doi:10.1016/j.freeradbiomed.2011.12.022
Good George, I think Tucker is right, LA is the key to his "diseases of civilization" at least as bad as sugar and refined carbs.
I have been chasing the effect of PUFAs in cancer. The fascinating thing here is the high peroxidation potential, the very high presence in cardiolipin in a bad diet and the cell damage from processing (homogenization, high heat and pressure processing).
Cell damage seems to be the key that kicks off the higher levels of peroxidation producing the higher levels of oxidative damage (there are two levels of peroxidation according to Spiteller, enzymatic and strictly chemical - the chemical due to processing is the real killer).
The speculation is the enormous cell damage during processing ensures a substrate of damaged cells which become deranged and migrate towards cancer through the ETC/membrane damage and impaired oxphos. HNE is a major culprit here also. There is a wealth of associational evidence for this but as far as I know no mechanistic link to cancer yet.
BTW this is the start of an email I sent to Tom Seyfried on this idea (I will spare you the detail) which he agreed was possible but not something they are chasing right now.
Thank you for responding to my previous email.
I am very interested in the link between industrial linoleic acid processing and cancer. I have not found a detailed presentation of the topic and especially of the key features so I have attempted one. There is much on LA and cancer of course but there appears to be no detailed mechanistic link extant between your Metabolic Theory and the intensive industrial processing of LA.
Examination of evidence provided by G. Spiteller et al, yourself and other researchers involved in gene mutation in cancers and the association of linoleic acid to cancer through many paths has convinced me that the link is profound. My sense is that the ultra processing of linoleic acid containing substances involves a degree of freedom more intense than that found in biological systems and this processing leaves a wasteland of damaged cells and mitochondria that gets incorporated into human tissue upon consumption. This provides a pregnant substrate for the development of cancer, possibly in conjunction with diabetes, which can be demonstrated in the laboratory. Your theory provides me with a natural bridge whereas somatic mutation does not. This link can explain all the important features of cancer including the appetite for glucose and glutamine and the massive and seemingly random mutations.
Basically, the argument is:
1. There exists significant association of LA to cancer, including historical, epidemiological and laboratory evidence.
2. There is chemical evidence of a degree of freedom in heat processing of LA, not typically found in biological systems, that produces profound injury to tissue, particularly the action of lipoperoxidation by chemical rather than enzymatic means.
3. The ingestion of this tissue provides a vast substrate for cancer.
4. The link provides support for your Metabolic Theory by providing direct evidence of the causation flow from lipid peroxidation induced mitochondrial injury to changed respiration, a rationale for the emergence of hexokinase II and to random nuclear mutation.
5. Finally I believe it is possible to test the link in the laboratory.
You will notice I have borrowed liberally from yourself, G. Spiteller, Harumi Okuyama and others and have been led by Tucker Goodrich and Peter Dobromylskyj in this effort to map out the details. The language is obtuse to be sure, but necessary. I believe there is a message there and I have included the authors own description where it serves the narrative. I am hoping you will take the few minutes necessary to glance over it.
I apologize if this is all old hat to you but I have not seen it described explicitly so it is just faintly possible it has evaded notice. I am continuing to develop the argument as there is a wealth of detail to be elucidated but I believe there is sufficient here to bring it to your notice. Best of luck in your continued efforts.
the combination of high PUFAs and beta-oxidation lowering sugar intakes really can provide a 1-2 punch to explain much of how we see metabolic syndrome or cancer develop
great post george
Good stuff Tim,
PUFA can be used by cancers to make cholesterol and promote angiogenesis
Raphi there may be a threshold effect; so that the dose of PUFA is a condition but not the only condition; there could even be an n-shaped curve if higher intakes start to drive beta-oxidation via PPAR-alpha induction.
Tim Foxon said: „LA is the key to his "diseases of civilization" at least as bad as sugar and refined carbs.“ Really? And what about this:
Hi George, I've been reading and re-reading this for a while - so many of these things depend on quite subtle shifts in reaction rates, feedbacks etc. Where you quote this "In peripheral tissues, insulin normally downregulates the hormone sensitive lipase (HSL) enzyme responsible for hydrolysis of stored triglycerides from free fatty acids within adipocytes. In patients who are insulin resistant, this enzyme is no longer suppressed", isn't a typical outcome of insulin resistance an elevated and prolongued high insulin level but weight gain? (ie more storage of lipid in adipocytes). Is this a timing thing perhaps wrt levels of lipid available in the fed state vs post-prandial - as insulin dies down again is relatively more ffa released into circulation?
I'm wondering that, using above mechanisms, how a sugar or fructose supplemented low-fat chow can stimulate the development of fatty liver, and how it can be prevented by antibiotics?
E.g. as in this study:
Bergheim, Ina, Synia Weber, Miriam Vos, Sigrid Krämer, Valentina Volynets, Seline Kaserouni, Craig J. McClain, and Stephan C. Bischoff. “Antibiotics Protect against Fructose-Induced Hepatic Lipid Accumulation in Mice: Role of Endotoxin.” Journal of Hepatology 48, no. 6 (2008): 983–92. https://doi.org/10.1016/j.jhep.2008.01.035
this could be one way-
Fructose conversion to acetate by bacteria; also known as a cause of soft-drink ketoacidosis
here's another possible explanation.
Choline protects against sugar NAFLD in rodents, and rodent diets are made borderline choline deficient for testing the effect of different nutrients on NAFLD/NASH
So - it's likely that fructose or sugar, being more lipogenic than glucose, increase the requirement for choline.
Bacteria that convert choline to TMAO reduce choline availability.
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