Steatohepatitis induced by intragastric overfeeding in mice.

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 +/- 27 vs. 13 +/- 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFalpha and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARgamma, LXRalpha) was increased, whereas that of a lipolytic nuclear factor PPARalpha was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.

Hepatoprotective mechanisms of Yan-gan-wan.

BACKGROUND AND AIMS: : A herbal prescription, Yan-gan-wan (YGW), has been known to offer hepatoprotective effects in Asian countries for years. This study investigated its mechanisms of action. METHODS: : The effects of YGW on CCl(4) induced liver damage were tested in mice and cultured hepatocytes. Microarray analysis screened genes affected by YGW. YGWs effects on the expression of cytochrome P450 (CYP) 2E1 and other isozymes were determined. YGWs effects on TNFalpha expression and NF-kappaB activation in Kupffer cells (KC), and TNFalpha promoter activity in RAW264.7 cells, were also assessed. RESULTS: : Administration of YGW reduced the plasma ALT, centrilobular necrosis, neutrophilic infiltration, and TNFalpha mRNA in the livers of mice acutely given CCl(4). The in vivo herb treatment reduced ALT release and necrosis of isolated hepatocytes directly exposed to CCl(4). Microarray analysis demonstrated marked reductions in CYP4A10 and 4A14 by YGW but no changes in other CYP isozymes as confirmed by immunoblot analysis. The herb treatment suppressed LPS-stimulated TNFalpha release in vivo and by cultured KC. Direct addition of the aqueous herb extract suppressed NF-kappaB activation by KC and TNFalpha promoter activity in RAW cells under LPS stimulation. This activity to suppress TNFalpha expression was largely separated into gel filtration fractions with the molecular size of 102-107Da. YGW also attenuated liver fibrosis induced by chronic treatment of CCl(4) or porcine serum. CONCLUSIONS: : The protective effects of YGW on CCl(4) hepatotoxicity are due in part to inhibition of KC NF-kappaB activation and TNFalpha expression by small water soluble molecules, and may also be related to suppressed hepatic expression of CYP4A10 and 4A14 that are considered as alternative prooxidant cytochromes.