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)

Hepatic complications are common in patients receiving total parental nutrition (TPN) and who have no underlying liver disease. In the present study we examined the hypothesis that endotoxin (LPS) or possibly TNF derived from the overgrowth of intestinal gram-negative bacteria is responsible for TPN-associated hepatic steatosis, and that bowel decontamination and specific anti-LPS activity of polymyxin B will reduce fatty infiltration of the liver during TPN. Forty-five male Sabra rats underwent jugular vein cannulation, were placed in metabolic cages, and were randomized into five groups. Group I was continuously infused with normal saline and allowed food ad lib, while group II-V were continuously infused with a TPN formula containing 4.25% amino acids and 25% dextrose for a total of 36 calories and 3.0 g protein per 100 g body weight/day. In addition, groups III-IV were also treated by oral polymyxin B while Groups IV and V received a combination of neomycin, metronidazole, and vancomycin (NMV). Thus, Group III received polymyxin B, Group IV received both polymyxin B and NMV, while Group V received NMV only. On Days 7-8 of the study, all animals were sacrificed and spontaneous production of TNF by peritoneal macrophages, bacterial translocation to mesenteric lymph nodes, culture of the cecum, and fat, triglyceride, and cholesterol contents of the liver were determined. All groups infused with TPN exhibited higher levels of total fat, triglycerides, and cholesterol compared to the free feeding control group (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat. 190 98

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF-alpha expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF-alpha and cytokines [interleukin (IL)-6, IL-10, transforming growth factor-beta (TGF)-beta, IL-12, and interferon-gamma] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol-containing diets for 6 weeks. Cytokine expression in the ethanol-fed groups was compared with that of pair-fed controls rats that had received isocaloric amounts of a similar, ethanol-free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair-feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol-fed rats also expressed more leptin, a TNF-alpha-inducible mRNA that encodes an appetite-suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF-alpha as a potential mediator of the nutritional-metabolic aberrations that often accompany chronic alcohol intake, even in the absence of advanced liver disease.
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PMID:Chronic ethanol consumption induces the production of tumor necrosis factor-alpha and related cytokines in liver and adipose tissue. 972 42

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor alpha (TNF-alpha). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-alpha improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-alpha activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-alpha messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor kappaB (NF-kappaB), the target of IKKbeta, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid beta-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.
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PMID:Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. 1288 98

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

The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion.
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PMID:Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. 1695 Jan 34

Intragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well-known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, or increased S-adenosylmethionine.
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PMID:Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. 1695 78

The proinflammatory cytokine TNF has a pivotal role in liver pathophysiology because it holds the capacity to induce both hepatocyte cell death and hepatocyte proliferation. This dual effect of TNF on hepatocytes reflects its ability to induce both nuclear factor kappaB (NF-kappaB)-dependent gene expression and cell death. Multiple studies have demonstrated the crucial role of the transcription factor NF-kappaB in the decision between life and death of a hepatocyte. Massive hepatocyte apoptosis preceding embryonic lethality in NF-kappaB-deficient mice constituted the first indication of an essential antiapoptotic function of NF-kappaB in the liver. Although many studies confirmed this crucial cytoprotective role of NF-kappaB in adult liver, a number of genetic studies recently obtained conflicting results on the exact role of NF-kappaB in different mouse models of TNF hepatotoxicity, demonstrating that caution should be taken when interpreting studies using different NF-kappaB-deficient mice in distinct models of liver injury. Recent reports showing a role for hepatic NF-kappaB activation in the proliferation of malignant cells during hepatocarcinogenesis, and in the progression of fatty liver diseases to insulin resistance and type 2 diabetes mellitus demonstrate that NF-kappaB can also have more detrimental effects in the liver. Moreover, its role in the development of the metabolic syndrome emphasizes that hepatic NF-kappaB activation might also have adverse effects on the endocrine system. Therefore, understanding the regulation of hepatic TNF signaling and NF-kappaB activation is of critical therapeutic importance. In this review, we summarize how studies on the role of NF-kappaB in different mouse models of liver pathologies have contributed to this understanding.
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PMID:Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. 1743 Dec 29

Worldwide approximately 200 million people are chronically infected with hepatitis C virus (HCV). Chronic HCV infection represents the leading cause of liver cirrhosis and the main indication for liver transplantation in the western world. In addition, chronic HCV infection is associated with numerous clinical manifestations, including type 2 diabetes. An obvious and frequently suggested explanation for the connection between HCV infection and type 2 diabetes is that cirrhosis by itself causes insulin resistance. However, the prevalence of type 2 diabetes in HCV cirrhosis is higher than in HBV cirrhosis (23.6% vs 9.4%). This suggests that HCV infection by itself can lead to insulin resistance and predispose to the onset of type 2 diabetes. First, HCV core protein induces hepatic steatosis by inhibition of microsomal triglyceride transfer protein and hepatic steatosis causes insulin resistance. Secondly, HCV core protein inhibits, through elevation of TNF-alfa and other factors, the insulin-signalling pathways causing insulin resistance. Moreover, recent data strongly suggest that insulin resistance is an important predictor of poor response to antiviral therapy in chronic hepatitis patients treated with peginterferon plus ribavirin.
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PMID:Hepatitis C and insulin resistance: mutual interactions. A review. 1754 92

Rising levels of alcohol consumption in the UK are leading to substantial increases in morbidity and mortality from liver disease. Drinking is starting at an earlier age with binging an increasing common pattern, and women are overtaking men in the consumption. Manifestations of liver damage range from fatty liver to end-stage cirrhosis, but it is the increasing number of cases presenting with an acute alcoholic hepatitis (AAH) that are the cause for greatest concern. Development of well-validated prognostic scoring systems (Maddrey Modified Discriminant Function, Glasgow Alcohol Score) makes it possible to select those patients with AAH who are most likely to respond to corticosteroids. The results of early pilot studies of a number of anti-TNF agents are encouraging and with infliximab, reduction in portal pressure has been demonstrated to be consequent on controlling inflammatory processes in the liver. For those deteriorating to the stage of liver failure, artificial liver support with MARS is of value in correcting major pathophysiological disturbances and as a bridge to liver transplantation, the results of which both for end-stage alcoholic cirrhosis and for AAH--of which there is limited experience, are excellent. Even as the stringent regulatory measures needed to control rising alcohol consumption are introduced by government, the burden of liver disease in the UK will remain high for years to come.
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PMID:The pervading influence of alcoholic liver disease in hepatology. 1838 13

Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFalpha. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wild-type adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.
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PMID:TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase. 1920 49


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