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)

Activation of methionine to S-adenosylmethionine is depressed in alcoholics. Its repletion opposes alcoholic liver cirrhosis in baboons, decreases mortality in cirrhotic patients, and opposes oxidative stress resulting from cytochrome P4502E1 (CYP2E1) induction by alcohol, ketones, and fatty acids. Their excess causes alcoholic and nonalcoholic steatohepatitis. CYP2E1 is also induced in Kupffer cells, promoting their activation and release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. The TNF-alpha inhibitor pentoxifylline decreased mortality from alcoholic hepatitis. Polyenylphosphatidylcholine (PPC), an antioxidant phosphatidylcholine mixture extracted from soybeans, 50% of which consists of the highly bioavailable dilinoleoylphosphatidylcholine, restores phospholipids of the damaged membranes and reactivates their enzymes, including phosphatidylethanolamine methyltransferase, needed for phospholipid regeneration. In baboons, PPC prevented cirrhosis by stimulating collagenase and by opposing lipid peroxidation, which produces the fibrogenic hydroxynonenal. PPC was beneficial in patients with alcoholic hepatitis, and it opposed fibrosis in heavy drinkers and decreased aminotransferases in patients with hepatitis C. The antioxidant silymarin also successfully opposed alcoholic cirrhosis in baboons and in some but not all clinical trials; this effect also pertains to a-tocopherol. The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically.
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PMID:New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. 1472 Apr 55

Fatty liver is a common predisposing risk factor for postoperative liver failure and accounts for most discarded livers during triage of donors. We investigated the effect of heat shock preconditioning (HPc) on recipient survival in a rat fatty liver transplantation model. Fatty liver donor rats were exposed to brief whole-body hyperthermia (10 minutes at 42.5 degrees C) and allowed to recover. HPc induced heat shock proteins (HSPs) (HSP72, HSP90, and heme oxygenase [HO]-1) in donor livers, with levels peaking 12 to 48 hours after HPc. Subsequently, donor livers were harvested 24 hours after HPc, placed in cold storage for 10 hours, and transplanted into normal rats. At 3 hours posttransplantation, HPc reduced serum liver enzymes in the recipients and almost completely suppressed the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. Histologic evaluation 3 and 24 hours after transplantation showed that HPc significantly reduced hepatic inflammation and hepatocellular necrosis without affecting the steatotic appearance of hepatocytes. One week after transplantation, control non-heat-shocked and heat-shocked fatty liver recipients exhibited survival rates of less than 10% and more than 80%, respectively. The evaluation of the survival of recipients receiving fatty livers at different times after HPc showed that the protective effect of HPc was significant when donor livers were transplanted 3 to 48 hours after HPc, with the maximum effect seen 6 to 48 hours after HPc. In conclusion, HPc is a promising avenue to salvage rejected donor fatty livers and enhance the survival rate of fatty liver recipients. We estimate that this technique could increase the annual donor pool by 600 livers.
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PMID:Technique for expanding the donor liver pool: heat shock preconditioning in a rat fatty liver model. 1476 65

Alcoholic liver disease is associated with a state of hepatic fatty acid overload. We examined the effect of ethanol and different types of dietary fat on the expression of mRNA for liver fatty acid binding protein (L-FABP), peroxisome proliferator-activated receptor-alpha (PPARalpha), and peroxisomal fatty acyl CoA oxidase (FACO). Four groups of rats (n = 5) were fed intragastrically, a liquid diet with or without ethanol (10-16 g/kg/day) for 4 weeks. Pair-fed controls received isocaloric amounts of dextrose. The source of fat was either corn oil or fish oil. Ethanolfed rats developed fatty liver, necrosis, and inflammation; the changes were more severe in the fish oil-ethanol (FE) rats. PPARalpha mRNA levels were not different between groups, although there was a trend toward increased levels in ethanol-fed rats. We calculated L-FABP/PPARalpha and FACO/PPARalpha ratios as a measure of FACO and L-FABP up-regulation relative to PPARalpha expression. Both FACO/PPARalpha and L-FABP/PPARalpha ratios were significantly decreased in FE rats. However, only L-FABP/PPARalpha was decreased in corn oil plus ethanol rats. Also, the level of L-FABP/mRNA correlated inversely with the degree of fatty liver in ethanol-fed rats. Since expression of PPARalpha response genes was impaired in ethanol-fed rats, we determined whether activation of PPARalpha would normalize the PPARalpha response and prevent the pathological changes in ethanol-fed rats. Treatment with clofibrate, a PPARalpha-activating ligand, led to a marked decrease in fatty liver and complete abrogation of necroinflammatory changes in FE rats. Also, nuclear factor kappaB activation and up-regulation of tumor necrosis factor-alpha and cyclooxygenase-2 was also abolished in clofibrate-treated rats. We conclude that adaptive gene regulation of FACO and L-FABP by PPARalpha is impaired in ethanol-fed rats and that treatment with clofibrate, a PPARalpha ligand, prevents alcohol-induced pathological liver injury, possibly by reversing the above changes.
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PMID:Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. 1501 35

Dietary fish oil rich in (n-3) fatty acids plays an important role in reducing abnormalities associated with the metabolic syndrome and mortality from coronary heart disease. We investigated the effects of dietary fish oil on the metabolic syndrome in a high-sucrose-fed rat model. The model was achieved by the administration of 30% sucrose in drinking water in male Wistar rats during 21 weeks. After the metabolic syndrome rat model was established, fish oil was administered during 6 weeks. The metabolic syndrome rats showed significant increases in body weight, systolic blood pressure, serum insulin, total lipids, triacylglycerols, cholesterol, free fatty acids, LDL, total proteins, albumin, and serum tumor necrosis factor-alpha (TNF-alpha). They also presented abdominal and epididymal fat accumulation and fatty liver. After fish oil diet administration, metabolic syndrome rats had a significant reduction in blood pressure, serum insulin, triacylglycerols, cholesterol, free fatty acids, and total lipids, but no change was observed in TNF-alpha concentration or fat accumulation. In conclusion, fish oil reversed the alterations on metabolic parameters and blood pressure exerted by sucrose administration, although it had no effect on TNF-alpha production and adiposity. This confirms the theory that the molecular etiology of the metabolic syndrome is multifactorial, as is the effect of n-3 polyunsaturated fatty acids (PUFAs) upon it, having complex and multifaceted actions.
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PMID:Effects of fish oil on hypertension, plasma lipids, and tumor necrosis factor-alpha in rats with sucrose-induced metabolic syndrome. 1515 41

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-alpha, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.
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PMID:Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. 1527 42

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that resembles alcohol-induced fatty liver disease(AFLD), but which develops in individuals who are not heavy drinkers. In people, NAFLD is associated strongly with obesity,insulin resistance, and dysmetabolic syndrome, but the exact mechanisms that promote liver disease in this clinical context remain poorly understood. The proinflammatory cytokine, funor necrosis factor alpha is known to be a key mediator of AFLD. This article discusses clinical and experimental evidence that tumor necrosis factor plays a role in the pathogenesis of insulin resistance syndromes, including nonalcoholic fatty syndromes, including nonalcoholic fatty liver disease.
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PMID:Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. 1533 Oct 67

Alcoholic liver disease (ALD) presents considerable challenges to clinicians. Screening for alcohol abuse and alcoholism should be routine and repeated annually with close attention to signs and symptoms of liver disease. In patients with evidence of liver dysfunction or injury, consideration should be given to performance of liver biopsy for diagnosis and prognosis and prior to initiation of medication with the potential for significant side effects. Therapy depends on the spectrum of pathological liver injury: alcoholic fatty liver, alcoholic hepatitis, and cirrhosis. Abstention is the foundation of therapy for an alcohol problem. Alcoholic fatty liver should improve with abstention, but the similarity to the pathogenesis of nonalcoholic fatty liver and potential for progressive injury merits consideration of lipotropic agents. The continuing mortality, poor acceptance of corticosteroids, and identification of tumor necrosis factor-alpha (TNF-alpha) as an integral component has led to studies of pentoxifylline and, recently, anti-TNF antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidant therapy of alcoholic cirrhosis has significant promise but will require large clinical trials.
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PMID:Diagnosis and therapy of alcoholic liver disease. 1534 2

Fatty liver, formerly associated predominantly with excessive alcohol intake, is now also recognized as a complication of obesity and an important precursor state to more severe forms of liver pathology including ischemia/reperfusion injury. No standard protocol for treating fatty liver exists at this time. We therefore examined the effects of 10 days of interleukin 6 (IL-6) injection in 3 murine models of fatty liver: leptin deficient ob/ob mice, ethanol-fed mice, and mice fed a high-fat diet. In all 3 models, IL-6 injection decreased steatosis and normalized serum aminotransferase. The beneficial effects of IL-6 treatment in vivo resulted in part from an increase in mitochondrial beta oxidation of fatty acid and an increase in hepatic export of triglyceride and cholesterol. However, administration of IL-6 to isolated cultured steatotic hepatocytes failed to decrease lipid contents, suggesting that the beneficial effects of IL-6 in vivo do not result from its effects on hepatocytes alone. IL-6 treatment increased hepatic peroxisome proliferator-activated receptor (PPAR) alpha and decreased liver and serum tumor necrosis factor (TNF) alpha. Finally, 10 days of treatment with IL-6 prevented the susceptibility of fatty livers to warm ischemia/reperfusion injury. In conclusion, long-term IL-6 administration ameliorates fatty livers and protects against warm ischemia/reperfusion fatty liver injury, suggesting the therapeutic potential of IL-6 in treating human fatty liver disease.
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PMID:Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. 1538 16

Nonalcoholic fatty liver disease (NAFLD) is the preferred term to describe the spectrum of liver damage ranging from hepatic steatosis to steatohepatitis, liver fibrosis, and cirrhosis, and it is emerging as the most common liver disease in industrialized countries. Thus, the discovery of food components that would ameliorate NAFLD is of interest. Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid, has attracted considerable attention because of its potentially beneficial biological effects both in vitro and in vivo. We tested whether dietary CLA protects Zucker (fa/fa) rats from hepatic injury. After 8 wk of feeding, hepatomegaly, hepatic triglyceride (TG) accumulation, and elevated hepatic injury markers in plasma were markedly alleviated in CLA-fed Zucker rats compared with linoleic acid-fed (control) rats. These effects were attributed in part to the enhanced hepatic activities of carnitine palmitoyltransferase, a key enzyme of fatty acid beta-oxidation, and microsomal TG transfer protein, an important factor for lipoprotein secretion due to the CLA diet. We previously reported that the severe hyperinsulinemia in control Zucker rats was attenuated in CLA-fed rats due to an enhanced level of plasma adiponectin, which improves insulin sensitivity. In the present study, the adiponectin concentration was increased and the mRNA expression of tumor necrosis factor-alpha, an inflammatory cytokine, was markedly suppressed in the liver of CLA-fed Zucker rats. We speculate that the enhanced level of liver adiponectin may prevent the development and progression of NAFLD in CLA-fed Zucker rats.
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PMID:Dietary conjugated linoleic acid alleviates nonalcoholic fatty liver disease in Zucker (fa/fa) rats. 1562 25

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


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