Genetic ablation of Them1 in mice decreases hepatic FFA concentrations and improves glucose tolerance in high fat fed mice, putatively

by reducing endoplasmic reticulum Seliciclib manufacturer stress. However, because Them1-deficient mice also exhibit increased energy expenditure and resistance to diet-induced obesity, the contribution of Them1 expression in liver to NAFLD remains unclear. Aim: This study was designed to assess the specific contribution of hepatic Them1 expression to glucose metabolism in high fat fed mice. Methods: We designed conditional Them1 transgenic (c-Them1Tg) mice with Cre recombinase-dependent Them1 overexpression. Liver-specific Them1 transgenic (L-Them1Tg) mice were generated by infection with Cre recombinant adenovirus in c-Them1Tg mice. Control mice were infected with GFP recombinant adenovirus. Hepatic Them1 expression was assessed by immunoblot analysis. Mice were fed high fat (60% of kcal) diet for 2 w. Body composition was determined by magnetic resonance

spectroscopy. For tolerance tests (n=5 mice/group) to insulin (ITT), pyruvate (PTT) or glucose (GTT), beta-catenin signaling plasma glucose concentrations were determined in fasting mice and then periodically up to 90 min after i.p. injection of insulin (1 U/kg bw), pyruvate (2 mg/g bw) or glucose (1 mg/g bw) respectively. Mice were maintained on the high fat diet and allowed to recover for 7 days between each test. Results: L-Them1Tg mice exhibited a 3.4-fold increase

in the hepatic expression of Them1 compared with c-Them1Tg control. Total body weights, fat and lean masses of L-Them1Tg were similar to c-Them1Tg control mice, as were fasting plasma glucose concentrations. Indicative of decreased clearance rate of exogenous glucose, plasma glucose concentrations in L-Them1Tg mice were higher at each time point during MCE the GTT and the area under the curve was increased by 43% (c-Them1Tg, 16,532±1377, L-Them1Tg, 23,610±883; P=0.0025). By contrast, there were no differences in the ITT, which reflects whole body insulin sensitivity, or in the PTT, which estimates hepatic glucose production. Conclusion: Without altering body composition, liver-specific Them1 overexpression promotes glucose intolerance in high fat fed mice. These findings suggest a primary contribution of hepatic Them1 to the pathogenesis of NAFLD that is distinct from its function in suppressing energy expenditure. Disclosures: David E. Cohen – Advisory Committees or Review Panels: Merck, Genzyme; Consulting: Novartis, Aegerion, Dignity Sciences, Intercept; Speaking and Teaching: Merck The following people have nothing to disclose: Cafer Ozdemir Saturated fatty acids, such as palmitic acid (PA), play a key role in lipotoxicity and the pathogenesis of NASH. Sustained JNK activation is a key mechanism of lipotoxicity. Little is known about how JNK mediates the lethal lipotoxic effect of PA in hepatocytes.