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Background Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease ( ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. Methods C57 BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Results Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p- AMPK, ACOX1, CYP4A, and MTTP. Conclusions This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. [ABSTRACT FROM AUTHOR]

Background Peroxisome proliferator-activated receptor gamma ( PPAR γ) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPAR γ is up-regulated in steatotic liver of both animal and human. However, the effects of hepatic PPAR γ signaling on alcoholic liver disease ( ALD) remain elusive. Methods To determine the role of hepatic PPAR γ signaling on ALD, wild-type ( WT) and hepatocyte-specific PPAR γ knockdown ( PPAR γ∆ Hep) mice were fed a modified Lieber- De Carli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks to induce ALD. Blood parameters, hepatic steatosis, and inflammation were measured after 8-week alcohol feeding. Results Alcohol feeding to WT mice resulted in liver damage (alanine aminotransferase [ ALT], 94.68 ± 17.05 U/L; aspartate aminotransferase [ AST], 55.87 ± 11.29 U/L), which was significantly alleviated by hepatic PPAR γ knockdown ( ALT, 57.36 ± 14.98 U/L; AST, 38.06 ± 3.35 U/L). Alcohol feeding led to marked lipid accumulation and up-regulation of lipogenic genes including fatty acid transport protein 1 ( FATP1), acetyl- Co A carboxylase ( ACC), fatty acid synthase ( FASN), lipin1 (LIPIN1), diacylglycerol acyltransferase 1 ( DGAT1), and diacylglycerol acyltransferase 2 ( DGAT2) in the livers of WT mice. Knockdown of hepatic PPAR γ significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPAR γ in FL83 B cells significantly decreased ethanol ( Et OH)-, linoleic acid-, and Et OH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPAR γ also significantly reduced alcohol-induced inflammatory chemokine (monocyte chemotactic protein 1 [ MCP1], keratinocyte-derived chemokine [ KC], interferon gamma-induced protein 10 [ IP-10]) and inflammatory infiltration (lymphocyte antigen 6 complex, locus G [ Ly6 G], and F4/80). Conclusions The results suggest that hepatic PPAR γ signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation. [ABSTRACT FROM AUTHOR]