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Wednesday, 18 July 2012

Is a Diet High in Saturated Fat Good for the Liver?

If we follow the advice laid out in a previous post and increase fat while restricting PUFA, will the extra saturated fat be good or bad for our liver, HCV aside?

That depends, I suppose on whether you think alcohol and drugs and NAFLD are good models for virus-related liver damage. At present they are the only models we have. And we know that alcohol, acetaminophen, and fructose don't help people with Hep C. So I think they are very good models; all the mediators of liver damage from those causes are also present in the livers of people with Hep C (high ferritin, stellate cell activation, LPS sensitivity, lipid peroxidation, oxidative stress, and so on).
So personally I don't see it as any kind of leap to accept the relevance of papers like these. Besides, the proof of the suet pudding will appear in the eating thereof.

Hepatic Stellate Cells are the cells that make collagen in fibrosis. They are also called Ito cells, which explains why I missed all these Ito cell studies before (when I was collecting data on factors, including SFAs, that reduced hepatic stellate cell activity).
This is another line of evidence supporting the view that saturated fat in the diet is antifibrotic.
"When tallow was substituted for corn oil the Ito cells were not activated and the liver histology was normal".

Is it the PUFA restriction alone, or the addition of SFA? 
My reading of these papers is that both play a role. Even 5% calories as PUFA causes some fibrosis on a low-fat diet, but none when corn oil is added to beef fat or coconut MCT to give a similar ratio.

These may only be animal tests, but I assure you, if a supplement performed half as well as saturated fat in animals, it would out-sell Silymarin.
Besides, we are talking about something everyone eats already.

We used the intragastric feeding rat model for alcoholic liver disease to investigate the relationship between transforming growth factor (TGF)-beta 1 and inhibition of endothelial cell proliferation. Twelve groups of male Wistar rats (four to five rats per group) were fed ethanol or dextrose with either corn oil or saturated fat for 1-, 2-, and 4-week periods. All control animals were pair fed the same diets as ethanol-fed rats except that ethanol was isocalorically replaced by dextrose. In the ethanol-fed groups, nonparenchymal cells were isolated and TGF-beta 1 was measured in the nonparenchymal cell supernatant. Liver pathology and endothelial cell proliferation with an antibody to proliferating cell nuclear antigen were studied in all groups. Plasma TGF-beta 1 was measured in all rats. Pathological changes (fatty liver, necrosis, and inflammation) were observed only in the corn oil/ethanol-fed rats at 4 weeks. Significantly higher levels of TGF-beta 1 were seen in both plasma and nonparenchymal cell supernatant in rats fed corn oil and ethanol; plasma levels of TGF-beta 1 were not significantly different between the dextrose-fed controls and saturated fat/ethanol-fed rats. A significant inverse correlation (r = -0.89, P < 0.01) was seen between plasma TGF-beta 1 and the number of endothelial cells arrested at G1/S. Immunohistochemistry revealed the presence of TGF-beta 1 staining in interstitial macrophages only in rats fed corn oil and ethanol. The present study provides evidence for a role for TGF-beta 1 in inhibiting endothelial cell proliferation in experimental alcoholic liver disease. Arrest of endothelial cells may lead to their differentiation and/or to produce mediators that could stimulate other cells such as Ito cells. Sustained TGF-beta 1 may also lead to Ito cell production of extracellular matrix.

Alcohol Clin Exp Res. 1991 Dec;15(6):1060-6.
Effect of dietary fat on Ito cell activation by chronic ethanol intake: a long-term serial morphometric study on alcohol-fed and control rats.
Takahashi H, Wong K, Jui L, Nanji AA, Mendenhall CS, French SW.

Department of Internal Medicine, National Kurihama Hospital, National Institute on Alcoholism of Japan, Kanagawa.

We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio was found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA: 1.74 +/- 0.57, vs. 7.46 +/- 2.05, respectively, p less than 0.05, mean +/- SE). Ito cell fat also significantly decreased at 5 months of feeding (p less than 0.05). The fat/RER ratio in CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Alcohol Suppl. 1991;1:357-61.
Ito cell activation induced by chronic ethanol feeding in the presence of different dietary fats.
French SW, Takahashi H, Wong K, Mendenhall CL.

Department of Pathology, Faculty of Medicine, University of Ottawa, Ontario, Canada.

Bronfenmajer et al. (1966) first studied Ito cells in alcoholic hepatitis (AH) by light microscopy (LM). The number of Ito cells and the number of fat droplets were increased. Okanoue et al. (1983) found that Ito cells were reduced by LM but increased by electron microscopy (EM) in scars in AH. Ito cells were activated in scars (increased RER and decreased fat in Ito cells with transition to fibroblasts). Minato et al. (1983) showed that increased RER in Ito cells correlated with increased collagen synthesis of liver biopsies in vitro. Mak et al. showed increased RER correlated with the degree of fibrosis in alcoholic baboons (1984) and alcoholic cirrhosis in man (1988). French et al. (1988b) showed morphometrically that Ito cell fat was decreased and RER was increased only in scars but not in normal sinusoids so that Ito cell activation was restricted to the scars. There was no correlation of sinusoidally located Ito cell fat or RER with the amount of perisinusoidal collagen. In rats fed ethanol and a nutritionally adequate diet including corn oil (25% of calories) by intragastric cannula for five months the fatty liver progressed to focal central fibrosis, and Ito cell activation (fat/RER) was increased. When tallow was substituted for corn oil the Ito cells were not activated and the liver histology was normal. Thus, the type of dietary fat and the local environment (scars) are important factors in the activation of Ito cells by alcohol in vivo.

This paper suggests that flaxseed oil may not be the best omega-3 supplement for alcoholics: linolenic acid is the vegetable form of omega-3.
Besides, the benefits from PUFAs in Hep C (antiviral and metabolic) are only seen with DHA, arachadonic acid, and EPA (in descending order of potency), and these are only found in animal fats; oily fish, fatty red meat, organ meat, dairy fats, and egg yolks.
Life Sci. 2003 Jul 18;73(9):1083-96.
The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells.
Li J, Hu W, Baldassare JJ, Bora PS, Chen S, Poulos JE, O'Neill R, Britton RS, Bacon BR.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858-4354, USA.

Chronic ethanol consumption can result in hepatic fibrosis and cirrhosis. In addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters (FAEE) such as linolenic acid ethyl ester (LAEE). We have previously demonstrated that LAEE has promitogeinc and activating effects on hepatic stellate cells (HSC), but the mechanisms of these actions are not known. Intracellular signaling through MAP kinase pathways, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) can influence the activity of the transcription factor AP-1, while cell-cycle regulatory proteins such as cyclin E and cyclin-dependent kinase (CDK), play an important role in cell proliferation. In this study, we demonstrate that treatment of HSC with LAEE increases cyclin E expression and cyclin E/CDK2 activity, which may underlie the promitogenic effects of this compound. In addition, LAEE increases ERK and JNK activity, and these pathways play an important role in the activation of AP-1-dependent gene expression by LAEE. The stimulation of intracellular signaling pathways in HSC by this well-characterized ethanol metabolite may contribute to ethanol-induced hepatic fibrogenesis.

Dietary Saturated Fat Reduces Alcoholic Hepatotoxicity in Rats by Altering Fatty Acid Metabolism and Membrane Composition

Rats fed a saturated fat diet are protected from experimentally induced alcoholic liver disease, but the molecular mechanisms underlying this phenomenon remain in dispute. We fed male Sprague-Dawley rats intragastrically by total enteral nutrition using diets with or without ethanol. In 1 control and 1 ethanol group, the dietary fat was corn oil at a level of 45% of total energy. In other groups, saturated fat [18:82 ratio of beef tallow:medium-chain triglyceride (MCT) oil] was substituted for corn oil at levels of 10, 20, and 30% of total energy, while keeping the total energy from fat at 45%. After 70 d, liver pathology, serum alanine aminotransferase (ALT), biochemical markers of oxidative stress, liver fatty acid composition, cytochrome P450 2E1 (CYP2E1) expression and activity and cytochrome P450 4A (CYP4A) expression were assessed. In rats fed the corn oil plus ethanol diet, hepatotoxicity was accompanied by oxidative stress. As dietary saturated fat content increased, all measures of hepatic pathology and oxidative stress were progressively reduced, including steatosis (P < 0.05). Thus, saturated fat protected rats from alcoholic liver disease in a dose-responsive fashion. Changes in dietary fat composition did not alter ethanol metabolism or CYP2E1 induction, but hepatic CYP4A levels increased markedly in rats fed the saturated fat diet. Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress. In addition, reduced alcoholic steatosis was associated with reduced fatty acid synthesis in combination with increased CYP4A-catalyzed fatty acid oxidation and effects on lipid export. These findings may be important in the nutritional management and treatment of alcoholic liver disease. 

LOOK AT THIS TABLE: ... nsion.html

In fact, this paper should be read in full and all the figures and tables studied, because there are 4 groups of control rats fed various fats without alcohol, and what happens to them is as interesting as the effects with alcohol.

The control rats fed most saturated fats gained the least weight. Corn oil (high PUFA) was significantly more fattening than a mixture of beef fat and coconut MCTs, in a breed of rat designed to get fat on a "high fat" diet. 

And here's one for the vegetarians: Olive oil is quite good at suppressing fibrosis, though perhaps not as brilliant as beef fat. (note that mutton, goat, venison, cocoa, and dairy fats ought to be similar to beef and coconut).

When I say "saturated fat" I really include monounsaturated fat, as it behaves chemically in pretty much the same way; it takes more than one unsaturated bond in close proximity (there are two such bonds near to one another in omega-6 lineolic acid) to promote lipid peroxidation.

J Gastroenterol. 2009;44(9):983-90. Epub 2009 Jun 9.
Dietary olive oil prevents carbon tetrachloride-induced hepatic fibrosis in mice.
Tanaka N, Kono H, Ishii K, Hosomura N, Fujii H.

First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.

The specific purpose of this study was to investigate the effects of dietary olive oil on hepatic fibrosis induced by chronic administration of carbon tetrachloride (CCl(4)) in the mouse. In addition, the effects of oleic acid, a major component of olive oil, on activation of hepatic stellate cells (HSCs) were investigated in vitro.

Mice were fed liquid diets containing either corn oil (control, AIN-93) or olive oil (6.25 g/L) throughout experiments. Animals were treated with CCl(4) for 4 weeks intraperitoneally. The mRNA expression of TGF-beta1 and collagen 1alpha2 (col1alpha2) in the liver was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). The HSCs were isolated from mice, and co-cultured with either oleic acid (100 microM) or linoleic acid (100 microM) for 2 days. The expression of alpha-smooth muscle actin (alpha-SMA) was assessed by immunohistochemistry. In addition, the production of hydroxyproline was determined.

Serum alanine aminotransferase levels and the mRNA expression of TGF-beta and collalpha2 were significantly reduced by treatment of olive oil. Dietary olive oil blunted the expression of alpha-SMA in the liverand liver injury and hepatic fibrosis were prevented by treatment of olive oil. The number of alpha-SMA positive cells was significantly lower in HSCs co-cultured with oleic acid than in those co-cultured with linoleic acid. Concentration of hydroxyproline in culture medium was significantly lower in cells co-cultured with oleic acid than in the control.
Dietary olive oil prevents CCl(4)-induced tissue injury and fibrosis in the liver. Since oleic acid inhibited activation of HSCs, oleic acid may play a key role on this mechanism. 


George Henderson said...

Here's a recent blog by a clinician who has studied this effect:

Excellent read, and one to follow, as more is promised.

George Henderson said...

And here is a veritable feast of saturated-fat-good-for-the-liver research; the most complete collection so far, except they missed the "Ito cell" and "hepatic stellate cell" (same thing, different names, king of fibrosis) papers, which if included would double the size of this page: