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 steatosis may have a generally benign prognosis, either because most hepatocytes are not significantly injured or mechanisms to replace damaged hepatocytes are induced. To determine the relative importance of these mechanisms, we compared hepatocyte damage and replication in ethanol-fed and ob/ob mice with very indolent fatty liver disease to that of healthy control mice and PARP-1(-/-) mice with targeted disruption of the DNA repair enzyme, poly(ADP-ribose) polymerase. Compared to the healthy controls, both groups with fatty livers had significantly higher serum alanine aminotransferase values, hepatic mitochondrial H(2)O(2) production, and hepatocyte oxidative DNA damage. A significantly smaller proportion of the hepatocytes from fatty livers entered S phase when cultured with mitogens. Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice. Hepatocytes from PARP1(-/-) mice also had more DNA damage and reduced DNA synthesis in response to mitogens. However, neither mice with fatty livers nor PARP-1-deficient mice had atrophic livers. All of the mice with senescent mature hepatocytes exhibited hepatic accumulation of liver progenitor (oval) cells and oval cell numbers increased with the demand for hepatocyte replacement. Therefore, although hepatic oxidant production and damage are generally increased in fatty livers, expansion of hepatic progenitor cell populations helps to compensate for the increased turnover of damaged mature hepatocytes. In conclusion, these results demonstrate that induction of mechanisms to replace damaged hepatocytes is important for limiting the progression of fatty liver disease.
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PMID:Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. 1476 93

Nonalcoholic steatohepatitis (NASH) is a liver disorder that still demands improved treatment. Understanding the pathogenesis of NASH will help to develop novel approaches to prevent or treat this disease. In this study, we revealed a novel function of the aryl hydrocarbon receptor (AhR) in NASH. Transgenic or pharmacological activation of AhR heightened animal sensitivity to NASH induced by the methionine- and choline-deficient (MCD) diet, which was reasoned to be due to increased hepatic steatosis, production of reactive oxygen species (ROS), and lipid peroxidation. Mechanistically, the increased ROS production in AhR-activated mouse liver was likely a result of a lower superoxide dismutase 2 (SOD2) activity and compromised clearance of ROS. Activation of AhR induced tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiPARP) gene expression, depleted NAD(+), deactivated the mitochondrial sirtuin deacetylase 3 (Sirt3), increased SOD2 acetylation, and thereby decreased SOD2 activity. We also showed that Sirt3 ablation sensitized mice to NASH, whereas adenoviral overexpression of Sirt3 alleviated the NASH phenotype in AhR-transgenic mice. We conclude that activation of AhR sensitizes mice to NASH by facilitating both the "first hit" of steatosis and the "second hit" of oxidative stress. Our results suggest that the use of AhR antagonists might be a viable approach to prevent and treat NASH. Manipulation of the expression or activity of Sirt3 may also represent a novel approach to manage NASH.
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PMID:Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase Sirt3. 2350 3

The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin-resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9,-6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases.
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PMID:Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis. 2603 1