Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B(12), vitamin B(6), methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adeno-sylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B(12), alcohol, and selenium may modify the response to inadequate dietary folate.
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PMID:DNA methylation, cancer susceptibility, and nutrient interactions. 1552 34

BACKGROUND:: Nonalcoholic steatohepatitis is most often attributed to the effects of obesity, hyperlipidemia, diabetes mellitus and drugs. It is still unknown whether livers with steatohepatitis are more vulnerable to toxic damage. AIM:: To determine the effect of the hepatotoxicant thioacetamide in a rat nutritional model of hepatic steatohepatitis. METHODS:: Steatohepatitis was induced in rats by placing them on a methionine-choline deficient diet for 1 month. Thioacetamide was administered by three consecutive intraperitoneal injections (300mg/kg) at 24h intervals. RESULTS:: Following treatment with thioacetamide, the elevated serum levels of liver enzymes and blood ammonia, liver necroinflammation and the survival rate after 48h were not different between rats with normal or fatty liver. However, those parameters were significantly worse when steatohepatitis regressed after return to normal diet for 1 month (P < 0.01). Western blot analysis of hepatic extracts revealed no difference in cytochrome P4502E1 levels between livers with steatohepatitis and steatohepatitis after regression, suggesting that the enhanced hepatotoxicity after regression of steatohepatitis could not be attributed to increased cytochrome P4502E1. CONCLUSIONS:: In a nutritional model of steatohepatitis, rats with fatty liver were not more vulnerable than normal rats to liver damage induced by thioacetamide. However, liver damage was significantly more severe in rats with steatohepatitis after 1 month regression.
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PMID:Thioacetamide-induced hepatic damage in a rat nutritional model of steatohepatitis. 1558 79

Insulin resistance and increased cytochrome P450 2E1 (CYP2E1) expression are both associated with and mechanistically implicated in the development of nonalcoholic fatty liver disease. Although currently viewed as distinct factors, insulin resistance and CYP2E1 expression may be interrelated through the ability of CYP2E1-induced oxidant stress to impair hepatic insulin signaling. To test this possibility, the effects of in vitro and in vivo CYP2E1 overexpression on hepatocyte insulin signaling were examined. CYP2E1 overexpression in a hepatocyte cell line decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 in response to insulin. CYP2E1 overexpression was also associated with increased inhibitory serine 307 and 636/639 IRS-1 phosphorylation. In parallel, the effects of insulin on Akt activation, glycogen synthase kinase 3, and FoxO1a phosphorylation, and glucose secretion were all significantly decreased in CYP2E1 overexpressing cells. This inhibition of insulin signaling by CYP2E1 overexpression was partially c-Jun N-terminal kinase dependent. In the methionine- and choline-deficient diet mouse model of steatohepatitis with CYP2E1 overexpression, insulin-induced IRS-1, IRS-2, and Akt phosphorylation were similarly decreased. These findings indicate that increased hepatocyte CYP2E1 expression and the presence of steatohepatitis result in the down-regulation of insulin signaling, potentially contributing to the insulin resistance associated with nonalcoholic fatty liver disease.
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PMID:Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. 1563 82

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
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PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

Previous studies showed that chronic ethanol administration alters methionine metabolism in the liver, resulting in increased intracellular S-adenosylhomocysteine (SAH) levels and increased homocysteine release into the plasma. We showed further that these changes appear to be reversed by betaine administration. This study compared the effects of betaine and S-adenosylmethionine (SAM), another methylating agent, on ethanol-induced changes of methionine metabolism and hepatic steatosis. Wistar rats were fed ethanol or control Lieber-Decarli liquid diet for 4 wk and metabolites of the methionine cycle were measured in isolated hepatocytes. Hepatocytes from ethanol-fed rats had a 50% lower intracellular SAM:SAH ratio and almost 2-fold greater homocysteine release into the media compared with controls. Supplementation of betaine or SAM in the incubation media increased this ratio in hepatocytes from both control and ethanol-fed rats and attenuated the ethanol-induced increased hepatocellular triglyceride levels by approximately 20%. On the other hand, only betaine prevented the increase in generation of homocysteine in the incubation media under basal and methionine-loaded conditions. SAM can correct only the ratio and the methylation defects and may in fact be detrimental after prolonged use because of its propensity to increase homocysteine release. Both SAM and betaine are effective in increasing the SAM:SAH ratio in hepatocytes and in attenuating hepatic steatosis; however, only betaine can effectively methylate homocysteine and prevent increased homocysteine release by the liver.
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PMID:A comparison of the effects of betaine and S-adenosylmethionine on ethanol-induced changes in methionine metabolism and steatosis in rat hepatocytes. 1573 87

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT, which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle-RH7777 cells with constructs of wild-type PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (P<0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD.
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PMID:Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). 1701 64

Citrin, encoded by SLC25A13, is a liver-type mitochondrial aspartate-glutamate carrier (AGC), of which deficiency, in autosomal recessive trait, causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). NICCD patients have jaundice, hypoproteinemia, hypoglycemia, galactosemia, growth retardation, fatty liver and multiple aminoacidemia including citrulline, methionine, threonine and tyrosine. Some of the neonates who have experienced NICCD suffer from severe CTLN2 more than 10 years or several decades later. In CTLN2, neuropsychotic symptoms such as disorientation, aberrant behavior, coma and death are observed. Laboratory findings reveal hyperammonemia, citrullinemia, fatty liver and liver-specific decrease in a urea cycle enzyme, argininosuccinate synthetase (ASS). In some cases, hyperlipidemia, pancreatitis and hepatoma are accompanied with CTLN2. Citrin as a liver-type AGC plays a role in supplying aspartate to the cytosol for urea, protein and nucleotide synthesis by exchanging mitochondrial aspartate for cytosolic glutamate and proton, and transporting cytosolic NADH reducing equivalent to mitochondria as a member of malate aspartate shuttle essential for aerobic glycolysis. AGC is also important for gluconeogenesis from lactate. Although it is difficult to explain pathogenesis of the symptoms such as cholestasis in NICCD and liver-specific decrease of ASS protein in CTLN2 from the functions of the AGC, some are understandable by the loss of citrin functions. Many CTLN2 patients have been treated with a low protein and high carbohydrate diet and glycerol at the hyperammonemic coma. We argue that those treatments may result in fatty liver, hyperlipidemia, hyperammonemia and even death due to loss of the citrin functions. Loss of citrin first cause deficiency of aspartate in the cytosol, which results in an increase in cytosolic NADH/NAD(+) ratio and then activation of fatty acid synthesis pathway to compensate the aberrant ratio. This follows inhibition of fatty acid oxidation. The peculiar fondness for food of CTLN2 patients who like protein and dislike carbohydrate and sweets may be related to their metabolic requirements.
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PMID:Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. 1619 99

Toll-like receptors (TLR) recognize pathogen-derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine-choline deficient (MCD) diet-induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2 mice had significantly higher levels of serum ALT and greater TNF-alpha levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL-6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet-fed TLR2 mice was associated with reduced baseline and LPS-induced NF-kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2-mediated signals in liver injury.
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PMID:Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. 1634 99

Choline is important for assembly of very low density lipoproteins to export triglyceride from liver; however, studies to assess the effect of rumen-protected choline (RPC) supplementation on blood lipid metabolites in periparturient dairy cows have not been conducted. Thirty-two multiparous Holstein and 10 multiparous Jersey cows were randomly assigned to control or RPC treatments. A close-up diet was fed from approximately 3 wk before parturition through parturition, followed by a lactation diet from parturition through 49 d postpartum. For RPC, diets were top-dressed once daily with 60 g of a RPC product (25% choline as choline chloride) from 21 d before expected parturition through 21 d postpartum. Treatment did not affect dry matter intake either prepartum (12.0 vs. 12.1 kg/d for RPC and control, respectively) or during the first 3 wk postpartum (14.8 vs. 15.7 kg/d, respectively). Daily yields of 3.5% fat-corrected milk (39.4 vs. 37.4 kg/d), fat (1.46 vs. 1.38 kg/d), and protein (1.09 vs. 1.05 kg/d) did not differ statistically by treatment (RPC vs. control, respectively). Jersey cows in the control group had lower concentrations of nonesterified fatty acids and beta-hydroxybutyrate in plasma during d 1 to 10 postpartum than did other breed and treatment combinations. Cows fed RPC tended to have greater serum triglycerides prepartum (17.0 vs. 14.7 mg/dL) and lower plasma phospholipid at parturition (65.2 vs. 78.1 mg/dL) than control cows. Treatment did not affect cholesterol and phospholipid at other time points, but concentrations followed patterns of dry matter intake pre- and postpartum. Cows were in moderate body condition score (mean = 3.3) at the start of the study and did not lose excessive condition by 3 wk postpartum (mean body condition score loss = 0.5); therefore, cows might not have been at great risk for hepatic lipid accumulation. Additionally, calculated Met balance was negative postpartum; supplemental RPC might not have spared enough Met to produce a physiological benefit. More research is needed to determine how choline affects prevention or alleviation of fatty liver syndrome and to confirm potential differences between Holstein and Jersey cows.
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PMID:Lipid metabolite profiles and milk production for Holstein and Jersey cows fed rumen-protected choline during the periparturient period. 1635 82

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.
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PMID:Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years. 1636 67


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