Carbs Will Be Carbs, or, The Mystery of The Polyol Pathway

This little paper should have made a minor splash in the paleosphere last week, but no-one really knew what to do with it.
It has 20 authors. Success has a thousand fathers, they say. 

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

Abstract

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

The Polyol Pathway

To summarise - when extra glucose is consumed by mice, some of this is converted to sorbitol then to fructose. This is associated with elevation of AST and ALT. Mice that cannot convert convert glucose to sorbitol are protected from rises in fructose and liver enzymes. Therefore fructose is so bad for you that it even accounts for the metabolic harm of high glucose intakes.
"These studies show that glucose-mediated obesity, visceral fat accumulation, hyperinsulinaemia, hyperleptinaemia and fatty liver are all dependent in part on the conversion of glucose to fructose in the liver with the metabolism of fructose by KHK. In other words, the mechanism by which glucose induces its metabolic effects is largely dependent on fructose
metabolites resulting from the fructose generated from glucose by the polyol pathway".


But, one must insist - this is dietary glucose doing this, not dietary fructose. This is not evidence in support of the idea that fructose is the bad carb, and glucose is the good carb; it looks more like evidence that, in normal metabolisms, sugars are somewhat interchangeable.
If you consume an excess of glucose, hepatic metabolism will have to convert some of that excess to fatty acids. Palmitic acid will be synthesised, and some palmitic acid will be elongated to oleic acid (because you can't make a triglyceride with 3 SFAs - if there's no dietary MUFA, DNL oleate makes the process of esterification possible). But you'll also need glycerol, and fructose is said to be a better glycerol substrate than glucose (for some reason I don't understand, being hopeless at maths). Note the pyruvate as a source of fatty acids in the schema below - this could just as easily have come from glucose. Indeed, the acetyl-CoA to make fatty acids could have come from fatty acids. (This is what happens with linoleic acid in fatty liver disease. Indeed, this kind of futile cycling of lipid carbons seems to be a feature of NAFLD.)

In the context of hyperglycemia in the absence of dietary fructose, (one might speculate that) the generation of a little fructose makes sense, just as the elongation of palmitate to oleate makes sense, as a means of packing away energy from glucose into stable triglycerides (which can be exported from hepatocytes with VLDL, or stored more-or-less safely for a while) more easily than would otherwise be the case. Perhaps.

We fed the mice 10% glucose water and off they went.

The knock-out mice that couldn't change glucose into fructose consumed less glucose. The authors pulled out some KO mice (n=4) that ate as much as 4 non-KO mice, to show that the KO mice were healthier - fully protected against the metabolic harm of fructose/glucose - but this kind of post-hoc tactic is a bit suspect. Interestingly the KO mice had higher serum beta-hydroxybutyrate (ketone body) levels. I guess that energy had to go somewhere (is this at all relevant to the claims that potatoes elevate ketones?).


There are humans who cannot metabolise fructose or sorbitol.

"Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. Most adult patients do not have any dental caries".

Bill Lagakos says that his nutrition tutors spent all of five minutes on the polyol pathway; R.D. Feinman, who should know, states "I never saw the point or function of the polyol pathway".
Wild speculation aside, that's fair comment. The polyol pathway is useful for blinding diabetics, but it doesn't seem particularly essential for life. At most it might once have provided a slight buffer against hyperglycemia, but today we have far too many copies of the amylase gene and the polyol shock absorber, if that is what it was, is easily broken, making things worse. Is that any explanation? Some mysteries, it seems, are going to remain mysteries.


Fructose is a factor in fibrosis of chronic Hepatitis C: but it's not a biggie.

Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients.

Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology.

METHODS:

Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate-severe if ⩾20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification).

RESULTS:

Mean daily intake of total, industrial and fruit fructose was 18.0±8.7g, 6.0±4.7g, and 11.9±7.2g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p=0.02) and hypercaloric diet (p=0.001). CHC patients with severe liver fibrosis (⩾F3) reported a significantly higher intake of total (20.8±10.2 vs. 17.2±8.1g/day; p=0.04) and industrial fructose (7.8±6.0 vs. 5.5±4.2; p=0.01), not fruit fructose (12.9±8.0 vs. 11.6±7.0; p=0.34). Multivariate logistic regression analysis showed that older age (OR 1.048, 95% CI 1.004-1.094, p=0.03), severe necroinflammatory activity (OR 3.325, 95% CI 1.347-8.209, p=0.009), moderate-severe steatosis (OR 2.421, 95% CI 1.017-6.415, p=0.04), and industrial fructose intake (OR 1.147, 95% CI 1.047-1.257, p=0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH.

CONCLUSIONS:

The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC.

Excuse me, but OR 1.147 is not a huge correlation. It's as tiny as a red-meat-and-disease-of-your-choice correlation in a study run by vegans. What if they had looked at total carbohydrate? Or included fruit juice and high-GI glucose sources like bread and pasta? Do you think the OR would have been higher then? It was about OR 2.9 for carbohydrate and fibrosis in the last Italian diet study I read.

Yes, my header does say limit fructose. And fructose might have special powers to harm, it's just hard to distinguish how strong those are when the trend is to put all the blame on them. The usual sources of fructose - sugar, HFCS, fruit juice - are mainly dumping carbohydrate directly into circulation, like that 10% glucose water the mice drank. They are high GI carbs. Or they would be if F was also G. But F is also G, and G is also F. 
If we can learn anything from the polyol pathway, it is, that carbs will be carbs.

P.S. remember from the NASH posts how taurine is good for removing excess cholesterol from the liver? And generally hepatoprotective?

Sorbitol accumulation depletes taurine:
Prevention of sorbitol accumulation with the aldose reductase inhibitor sorbinil increased nerve taurine levels by 22% (p < 0.05) when compared with untreated diabetic animals. Thus, we have demonstrated an interdependence of organic osmolytes within the nerve. Abnormal accumulation of one osmolyte results in reciprocal depletion of others. Diabetic neuropathy may be an example of maladaptive osmoregulation, nerve damage and instability being aggravated by taurine depletion.

Gluten and Cross-Sensitivity as a Factor in Post-Interferon Malaise and Autoimmune Syndromes of Chronic Hep C

(Music: Charlie Parker Live at Storyville, 1953)

Coeliac and non-coeliac gluten sensitivity, conditions which can cause (apart from the classic syndrome) cirrhosis of the liver independent of viruses or alcohol, are hard to treat by simple removal of gluten grains, because gliadin sensitivity creates cross-sensitivity to peptides found in other foods.
(Hat-tip to Suppversity for posting about this).


Gliadin (Wheat), Casein (Milk), Secalin (Rye), Avenin (Oat), Kafirin (Sorghum), and Zein (Corn) peptides are prolamines (peptides with Pro-Pro bonds). But why does instant coffee feature at all? Well, coffee is a seed, but it doesn't appear to be a source of prolamines.
All of these cross-sensitivity prolamine allergens are also active at endorphin receptor sites; they are what is called exorphins. Wheat and milk can be addictive to persons who should be avoiding them, another reason coeliac is difficult to diagnose and treat. And roasted coffee beans also contain a compound which has endorphin receptor activity - except that it is an endorphin antagonist, and not a prolamine but a lactone formed from one of coffee's antioxidants.
There is no record of a link between coeliac disease and endorphins (at least, none that the cursory Google search that easily supplies all my other evidential links has uncovered), beyond the helpfulness of LDN (low dose Naltrexone) in CD recovery.
However, opioids (at least, the pharmaceutical ones) have two modes of action, one via the endorphin system, one via the immune system and TRL4 activity. Naltrexone is both an opioid antagonist and a TLR4 antagonist; and TLR4 is implicated in coeliac disease via non-gluten components of wheat, trypsin inhibitors.
(At about this point, the trail went cold. It would have been nice to link exorphins and TLR4, I had even dreamed about TLR4 antagonism and the benefits of coffee drinking, but it was not to be...)
Edit: here is a link between coffee and TLR4 inhibition, it's not about the exorphin, but there's hope for me yet.

Enlarged picture here

Coeliac and non-coeliac gluten sensitivity may be associated with Hepatitis C, and anecdotally a great many people with the virus find their health improves when avoiding the cross-reactive foods. Both coeliac disease (OR 3.1) and chronic HCV infection (OR 2-4) are associated with an increased rate of non-Hodgkin's lymphoma, and the autoimmune conditions commonly associated with coeliac are virtually identical to the extra-hepatic HCV syndrome. As an intracellular virus, HCV triggers the production of interferons, and interferon-alpha has a causitive role in coeliac. Coeliac disease has been triggered by INF-alpha treatment for HCV. However, gluten sensitivities are hard to diagnose and exist on a spectrum, with a significant proportion of people having some potential for sensitivity, and gluten sensitivity diseases may take time to develop. On average, cases of coeliac disease take 13 years to diagnose. This is plenty of time for someone to develop serious health problems or indeed die, without the involvement of gluten sensitivity being noticed.

(I have never been a fan of Interferon treatment for HCV; in my experience people who have avoided Interferon and treated themselves with diet and supplements tend to stay healthier overall than people who have done interferon but failed to respond to it. Indeed, I know people with chronic hepatitis C who stay healthy with no effort at self-treatment whatsoever. So far, the people I have known with HCV who have died of liver disease or needed transplants, other than alcoholics, are people who have taken Interferon but failed to clear the virus. People who do respond to Interferon can certainly improve, but this means that doctors prescribing Interferon need to be selective about who they offer it to. If it is prescribed to someone with no symptoms, or a low possibility of clearance, or a high risk of side effects on the basis that this is better than doing nothing, this is unlikely to be the case. Thankfully this question is becoming moot with the arrival of interferon-free treatments with a high rate of efficacy and minimal side-effects. Here is a grueling account of post-interferon problems.)

I think it entirely plausible that the post-treatment effects some people experience from Interferon therapy for HCV are mediated by the induction of sensitivity to wheat, milk, yeast, corn and other foods, and that the extra-hepatic and autoimmune syndromes of chronic hepatitis C have the same cause. This could include a wide variety of auto-immune conditions, not just gut disorders.
On the other hand, I am not in favour of eliminating so many foods from the diet that nutrition is compromised. Removing the main offenders - grains, legumes (also a source of trypsin inhibitors), yeast (bread and beer are the main sources of yeast), and milk (some dairy products low in casein, such as butter, may be OK), supplementing vitamin D and probiotics, and eating nutrient-dense foods mainly of animal origin for a while seems to be the best way to both heal the gut and reduce autoimmunity.

Another problem with grains, and with milk in people who are lactose intolerant, is SIBO, or an excess of bacteria in the small intestine. This is associated with progression of NASH and cirrhosis, and also with Vitamin B12 deficiency. It's a good fibre/bad fibre situation, with good fibres being those that ferment in the colon (large intestine).
Micheal Eades has just blogged about SIBO in the context of GERD, a common cause of eosophagitis (acid reflux, sore throat, difficulty swallowing, increased cancer risk).
Reading first the introduction to a vitamin primer, and then Protein Power, by Drs Michael and Mary Dan Eades first awakened me to the possibilities of low-carb, high fat diets for the treatment of inflammation and autoimmune disease. I'd like to thank the Drs Eades for writing books that became popular enough to become ubiquitous (and thus arrive at the Op Shops I get my books from) while remaining readable.
Here's one of my favourite NASH papers, just an abstract from a poster presentation at a conference - but how on earth does anyone get an omega 3:6 ratio of 1:144? Note that no-one here had 3:6 in or near the adaptive range of 1:1 - 1:5. 

POLYUNSATURATED FATTY ACID COMPOSITION IN ERYTHROCYTE LIPID MEMBRANES IN NASH: UNEXPECTED HETEROGENEITY IN THE N6-N3 RATIO

S. Caldwell*, C. Argo, A. Al-Osaimi, N. Shah, H. Lothamer, C. Harmon, J. Rodriguez
University of Virginia, Charlottesville, VA, USA. *shc5c@virginia.edu

Introduction and aim: Essential dietary polyunsaturated fatty acids (PUFA) include omega-6 (n-6) linoleic acid (18:2) which is metabolized to arachidonic acid (AA) and omega-3 (n-3) linolenic acid (18:3) which is metabolized to eicosapentanoic acid (EPA). Imbalance in secondary eicosanoids and prostaglandin metabolites of n-6 and n-3 PUFA are implicated in disorders related to the metabolic syndrome. Skeletal muscle PUFA influences systemic insulin sensitivity (Borkman 1993) and diets rich in omega-3 fatty acids are associated with diminished histological injury in NASH (Musso 2003). Erythrocyte membrane lipids reflect dietary intake of essential fatty acid over preceding months. We measured erythrocyte n-6:n-3 ratio in a cohort of patients as part of a larger study of omega-3 fatty acid therapy of NASH. 

Methods: 15 patients (10 female) underwent analysis of erythrocyte lipid composition using capillary gas chromatography (Metametrix, Duluth, GA) to determine the AA:EPA ratio. The mean age was 50 ± 13 years all with liver biopsy NAS score ≥ 5 and a range of non-cirrhotic fibrosis stages of stage 1 (n = 6), stage 2 (n = 5) and stage 3 (n = 4). 

Results: The mean AA:EPA was 65 ± 34 reflecting a relative excess of n-6 PUFA overall. However, a broad range was noted from 15 to 144 AA:EPA. Dividing the group into quintiles of the reference range, 9 of the patients fell into the highest (5^th) quintile (AA:EPA = 84 ± 30) compared to the remaining 6 patients (AA:EPA = 36 ± 16, p = 0.001). There was no statistically significant difference in the histological stage between these groups (fibrosis score = 2 ± 0.9 versus 1.7 ± 0.8) although the higher AA:EPA group was significantly older (55±12 versus 39±12, p=0.01). 

Conclusion: There is heterogeneity of AA:EPA in non-cirrhotic NASH patients and an age-related increase in n-6 to n-3 PUFA evident in the AA:EPA ratio of erythrocyte lipids. Further work is needed to understand if this reflects dietary differences and how this might influence response to omega-3 fatty acid therapy.

Here is a discussion of changing omega 3:6 in the US food supply: "The ratio of total n−6 to n−3 was 5.4 in 1909 and 9.6 in 1999". Average intake of omega 6 has always been sufficient but has become excessive, intake of omega 3 has always been inadequate.

The Elegant Solution

Peter D has been running a fantastic series on PUFAs and cancer. Lots of references to linoleic acid promoting the growth of hepatoma cells.

"In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells."

Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.

This passage also caught my eye:
"omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells. If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis."
(or for that matter, steatosis).

This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.



In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:

cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?

The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).⁵ Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (3, 4), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).

So, we have a paradox. And a solution.

In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.

Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.

This bit is for all the calorie nerds:

The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.

Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.

We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.

Oh no, not DNL too, I though that was all debunked, sorry folks

A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.


In conclusion: 

In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).

Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.

I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:

Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)


The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
    - Hunter S. Thompson

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)
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 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.

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.

Linoleic Acid (Omega 6 PUFA) promotes hepatic cholesterol accumulation - Bigtime.

Deeply deranged, they said.

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

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.