Pathogenesis Of Alcoholic Fatty Liver Research Articles

Pathogenesis of Alcoholic Fatty Liver a Narrative Review.

Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferator activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα, results in an inhibition of FA oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1)-driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very-low-density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor α (TNF α), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis contributes to the severity of ALD by increasing the metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen-associated molecular patterns (PAMPS) via specific Toll-like receptor (TLR) bacterial overgrowth leads to the translocation of bacteria. Endotoxins and toxic ethanol metabolites enter the enterohepatic circulation, reaching the liver and inducing the activation of the nuclear factor kappa-B (NFκB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in favour of necrosis.

Downregulation of mitogen-activated protein kinases (MAPKs) in chronic ethanol-induced fatty liver

Mitogen-activated protein kinases (MAPKs) are versatile proteins that have been suggested to be involved in the regulation of lipid metabolism. This study was designed to investigate the responses of MAPK signaling to chronic ethanol exposure in vivo and in vitro, and try to explore its role in the pathogenesis of alcoholic fatty liver (AFL). Mice were fed with Lieber-Decarli liquid diet (5% ethanol, w/v) for 4 weeks to induce fatty liver, and the chronological changes of MAPK phosphorylation were measured using western blotting. We found that chronic ethanol feeding led to accumulation of triglyceride (TG), decreased phosphorylation of MAPKs, decreased protein level of peroxisomal proliferator activation receptor α (PPARα), and increased protein expression of cytochrome P4502E1 (CYP2E1) in mice liver. In vitro study showed that overexpression of CYP2E1 blunted the response of MAPKs to ethanol, and MAPK phosphatase 1 (MKP-1) knockdown by siRNA led to upregulation of PPARα protein level. Lastly, epidermal growth factor (EGF), a well-known MAPK activator, significantly suppressed chronic ethanol-induced hepatic fat accumulation and decline of PPARα expression in mice liver. Collectively, MAPK suppression, possibly due to the activation of hepatic CYP2E1, may be involved in chronic ethanol-induced hepatic steatosis.

Estrogen-related receptor γ controls sterol regulatory element-binding protein-1c expression and alcoholic fatty liver

Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.

Aqueous Extract of Pepino (Solanum muriactum Ait) Leaves Ameliorate Lipid Accumulation and Oxidative Stress in Alcoholic Fatty Liver Disease.

Chronic alcohol intake leads to alcoholic fatty liver. The pathogenesis of alcoholic fatty liver is related to abnormal lipid accumulation, oxidative stress, endotoxins, and cytokines. Solanum muricatum Ait. (Pepino) is a plant food commonly cultivated in the Penghu island, Taiwan. Previous studies indicated that the aqueous extract of pepino was able to attenuate diabetic progression via its antioxidative and anti-inflammatory effects. However, the mechanisms of the antioxidative and anti-inflammatory effects of pepino leaf in preventing alcoholic fatty liver remain unknown. In this study, Lieber–DeCarli ethanol-containing liquid diet was used to induce alcoholic hepatic injury in C57BL/6 mice. The hepatoprotective effects and the related mechanisms of aqueous extract of pepino leaf (AEPL) were examined. Our results showed that 2% AEPL treatments protected the liver from ethanol-induced injury through reducing serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and triglyceride (TG) (all p < 0.05). AEPL had the effects in improving the ethanol-induced lipid accumulation in mice under histological examination. Molecular data indicated that the anti-lipid accumulation effect of AEPL might be mediated via inducing hepatic levels of phospho-adenosine monophosphate-activated kinase (p-AMPK) and peroxisome proliferator-activated receptor (PPAR)-α, and reducing the expressions of hepatic lipogenic enzymes, including sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) (all p < 0.05). AEPL also decreased hepatic levels of thiobarbituric acid relative substances (TBARS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, as well as the expression of nuclear factor kappa B (NF-κB) (all p < 0.05). Moreover, AEPL significantly elevated the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and glutathione (GSH) content compared to the ethanol-fed group (all p < 0.05). Our present study suggests that AEPL could protect the liver against ethanol-induced oxidative injury and lipid accumulation.

Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver

Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.

Resveratrol Ameliorates Alcoholic Fatty Liver by Inducing Autophagy.

Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved in inducing autophagy.

Resveratrol ameliorates lipid accumulation in HepG2 cells, associated with down-regulation of lipin1 expression.

The pathogenesis of alcoholic fatty liver (AFL) disease is associated with the excessive accumulation of lipids in hepatocytes as well as oxidative stress. Resveratrol (RES), a dietary polyphenol found in red wine and grapes, has been shown to protect against AFL disease. However, the precise mechanisms that lead to this protective effect remain elusive. In this study, we used HepG2 cells to investigate the effects of RES on lipid metabolism and the mechanisms underlying these effects. HepG2 cells were cultured with oleic acid and alcohol for 48 h to induce excessive lipid accumulation. Oil red O staining showed that administration of oleic acid and alcohol induced more lipid accumulation than was observed in the control group, and that RES (15, 45, or 135 μmol/L) treatment reduced intracellular lipid droplets. RES treatment also significantly attenuated hepatic steatosis and lowered levels of intracellular triglycerides (TG). Western blot analysis showed that RES enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and down-regulated the expression of sterol regulatory element-binding protein 1c (SREBP-1c) and lipin1. However, compound C, an AMPK inhibitor, reversed these effects of RES. In conclusion, RES reduced lipid accumulation and protected HepG2 cells. This effect may be associated with the down-regulation of SREBP-1c and lipin1 expression, increased levels of phosphorylated AMPK and ACC, and the activation of AMPK-lipin1 signaling.

The role of lipin-1 in the pathogenesis of alcoholic fatty liver.

The aim of this review was to focus on the knowledge of the role of lipin-1 in the pathogenesis of alcoholic fatty liver. Systematic review of animal clinical and cell level studies related to the function of lipin-1 on alcoholic fatty liver, alcoholic hepatitis and alcoholic liver cirrhosis disease. Ethanol could increase the expression of lipin-1 through the AMPK-SREBP-1 signaling and dramatically increase the ratio of Lpin1β to Lpin1α by SIRT1-SFRS10-Lpin1β/α axis in the liver. Moreover, research has shown that over-expression of lipin-1 could also remarkably suppress very low density lipoprotein-triacylglyceride secretion. Last, lipin-1 has potent anti-inflammatory property. In conclusion, lipin-1 has dual functions in lipid metabolism. In the cytoplasm, lipin-1β functions as a Mg(2+)-dependent phosphatidic acid phosphohydrolase (PAP) enzyme in triglyceride synthesis pathways. In the nucleus, lipin-1α acts as a transcriptional co-regulator to regulate the capacity of the liver for fatty acid oxidation and activity of the lipogenic enzyme. In hepatocytes of alcoholic fatty liver disease (AFLD), ethanol increases the expression of lipin-1 through the AMPK-SREBP-1 signaling and the Lpin1β/α ratio by SIRT1-SFRS10- Lpin1β/α axis. Of course, in addition to that, ethanol could also produce the PAP activity and interrupt the nucleus function of lipin-1. Furthermore, over-expression of lipin-1 could remarkably suppress very low-density lipoprotein-triacylglyceride (VLDL-TAG) secretion. In the end, endogenous lipin-1 has potent anti-inflammatory property. Increased synthesis of TAG, decreased fatty acid oxidation, impaired VLDL-TAG secretion and activated inflammatory factors act together to exacerbate the development of AFLD.

Advances in the roles of cytochrome P450 2E1 in the pathogenesis of alcoholic fatty liver

酒精性肝病(alcoholic liver disease,ALD)是过度饮酒引起的一类肝脏疾病,包括脂肪肝、肝炎、肝纤维化和肝硬化等.流行病学调查显示,ALD已成为严重影响中国居民健康的公共卫生问题[1].酒精性脂肪肝(alcoholic fatty liver,AFL)是ALD的早期阶段,因具有可逆性,曾一度被视为一种良性病变.然而近年的研究表明,脂肪变性的肝细胞对肿瘤坏死因子-α(tumor necrosis factor α,TNF-α)等敏感性增强,且部分AFL患者在戒酒后仍然会进展为肝炎、肝纤维化、甚至肝硬化[2-3].AFL是一种临床上的常见疾病,在饮酒量＞60 g/d的人群中发病率高达90％以上[4]。

CMZ Reversed Chronic Ethanol-Induced Disturbance of PPAR-α Possibly by Suppressing Oxidative Stress and PGC-1α Acetylation, and Activating the MAPK and GSK3β Pathway

BackgroundCytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms.MethodsMice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods.ResultsCYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ.ConclusionThese results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.

Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase–mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid–binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.

Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats

Background/Aims : To elucidate the role of microsomal triglyceride transfer protein (MTP) in the pathogenesis of alcoholic fatty liver, the effects of ethanol on MTP activity and gene expression were investigated. Methods and results : Male Sprague–Dawley rats fed an ethanol-containing liquid diet for 37 days, respectively, showed 2.9- and 4.9-fold increases in hepatic cholesterol and triglyceride content in comparison with rats fed an isocaloric ethanol-free diet ( P <0.01). Furthermore, a significant decrease in MTP activity and mRNA expression (by 27 and 58%, respectively) was observed after ethanol administration. Intravenous injection of human recombinant hepatocyte growth factor (hrHGF) on each of the last 7 days markedly suppressed ethanol-induced lipid accumulation in the liver. This inhibition of fatty change by hrHGF was accompanied by recovery of MTP activity and gene expression. No inhibitory effect of hrHGF on ethanol-induced acyl-CoA synthetase activation was observed. Experiments using human hepatoma-derived HepG2 cells indicated a direct positive effect of hrHGF on MTP gene expression as well as apolipoprotein B secretion. Conclusions : These results suggest that reduced MTP activity is crucial to development of alcoholic fatty liver, while promotion of MTP activity by HGF might serve as a therapeutic measure against alcoholic liver steatosis.

Multiple biochemical effects in the pathogenesis of alcoholic fatty liver.

The pathogenesis of alcoholic fatty liver is unknown, but several causes have been proposed based on biochemical findings. These include the metabolism of alcohol leading to a shift in the cytosolic [NAD+]/ [NADH] ratio to reduction, which in turn causes a direct inhibition of beta-oxidation and enhanced triacylglycerol formation via the [glycerol-3-phosphate]/[dihydroxyacetone phosphate] ratio. There are also chronic effects of ethanol on hepatic enzyme activities. Thus, increased activity of phosphatidate phosphohydrolase, an increased amount of fatty acid binding protein, decreased secretion of very low-density lipoprotein and impairment of the respiratory chain as a result of decreased protein synthesis or decreased amounts of ubiquinone could all lead to fat accumulation and steatosis. The interplay of each of these with nutritional and genetic factors would then lead to the heterogeneity of the severity and characteristics of the steatosis observed in human alcoholics.

ACTIVITY AND SUBCELLULAR DISTRIBUTION OF PHOSPHATIDATE PHOSPHOHYDROLASE (EC 3.1.3.4) IN ALCOHOLIC LIVER DISEASE

A micromethod was developed to assay the hepatic activity and subcellular distribution of phosphatidate phosphohydrolase (PAH, EC 3.1.3.4), an important regulatory enzyme in triacylglycerol synthesis, in human needle biopsy specimens. In normal liver PAH is predominantly cytosolic in distribution, but on treatment with oleic acid it shifts to the membranous compartments of the cell, its physiologically active site. The hepatic specific activity of PAH was similar in controls and patients with fatty liver but significantly more of the enzyme was associated with the membranous compartments in patients with severe alcoholic fatty liver. These observations may explain the enhanced rates of triacylglycerol synthesis observed in these patients and may be implicated in the pathogenesis of alcoholic fatty liver.

Effect of chronic ethanol feeding on the hepatic secretion of very-low-density lipoproteins

Using Triton WR-1339 to inhibit plasma metabolism of VLDL, hepatic secretion of VLDL was measured in vivo in control and alcohol-fed rats. The composition of VLDL secreted from livers of chronically alcohol-fed rats was compared with pair-fed controls. The results show that the cholesterol, esterified and nonesterified, as well as the triacylglycerol content of VLDL secreted by the alcohol-fed rats was significantly reduced; protein and phospholipid constituents of the VLDL were unaltered. The apoprotein components of the VLDL showed no apparent difference between the two groups. However, fatty-acid composition of VLDL triacylglycerol and phospholipids show a significant reduction in 20:4 and an increase in 18:2 fatty acids in the alcohol-fed rats. VLDL secretion rates by chronic alcohol-fed rats was reduced significantly compared to the control animals, and this observation has been implicated in the pathogenesis of alcoholic fatty liver.

Damage of rat liver sinusoidal endothelium by ethanol

Hepatic blood in normal rats is separated from the space of Disse and hepatocytes by an ultrastructural sieve formed by pores in the sinusoidal endothelium. This sieve has previously been shown to shield hepatocytes from circulating chylomicrons, the largest of the lipoproteins, which transport most triglycerides of dietary origin. In the present paper it has been shown that the chronic ingestion of ethanol leads to a significant enlargement of pores within the sieve, increasing them from a normal median diameter of 100 nm to 120 nm. A decrease in the normal sieving of perfused labelled large and small chylomicrons has also been noted. It is postulated that the decreased shielding of hepatocytes from large chylomicrons may be a factor in the pathogenesis of alcoholic fatty liver.

Nutritional Interrelationships among Vitamin E, Selenium, Antioxidants and Ethyl Alcohol in the Rat

Giving 20% alcohol as the sole drinking fluid delayed the onset of liver necrosis in rats fed a basal diet deficient in vitamin E and selenium. Addition of ethanol in vitro had no effect on the decline in respiration suffered by liver slices prepared from vitamin E- and Se-deficient rats. Determination of hepatic triglycerides in rats given alcohol for 5 to 6 weeks revealed that animals fed the basal vitamin E- and Se-deficient diet tended to have less fat in their livers than animals fed the same diet supplemented with either 500 ppm vitamin E or 0.3 ppm Se as Na2SeO3, or both. Certain fat-soluble antioxidants tended to diminish the hepatolipogenic action of ethanol, whereas vitamin E or Se did not. Examination of the time course of the development of alcoholic fatty liver showed that animals fed either the basal necrogenic diet or the basal diet supplemented with vitamin E and Se underwent a similar pathogenesis of alcoholic fatty liver for about 4 weeks. After this time, however, the vitamin E- and Se-deficient animals lost much of their liver fat, whereas the vitamin E- and Se-supplemented animals did not. The sparing action of alcohol on vitamin E- and Se-deficient animals appears inconsistent with a lipoperoxidative mechanism for chronic ethanol hepatotoxicity. The fact that vitamin E and Se tended to enhance the development of alcoholic fatty liver, whereas certain fat-soluble antioxidants did not, seems inconsistent with an antioxidant role for these two nutrients.