Functionally, isolated muscles from ALIOS diet-fed mice exhibited

Functionally, isolated muscles from ALIOS diet-fed mice exhibited reduced muscle strength in electrophysiological stud ies. Finally, mice with NAFLD had reduced serum levels o IGF-1 (281.7±40 pg/ml vs. 366±30 pg/ml in chow-fed mice p=0.04). CONCLUSION:

significant BMS-777607 decreased muscle mass and muscle strength was found in experimental NAFLD. This may be related to decreased IGF-1 hepatic production and/ or the low-grade inflammatory milieu present in obesity and steatohepatitis. Disclosures: The following people have nothing to disclose: Alex Ruiz, Daniel Cabrera, Pablo Quintero, Margarita Pizarro, Nancy Solis, Javiera Torres, Claudio Cabello-Ver-rugio, Enrique Brandan, Francisco Barrera, Marco Arrese Purpose: Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with nonalcoholic fatty liver disease. We recently demonstrated that exposure to the commercial PCB mixture, Aroclor 1260 (Ar) (20 mg/kg), worsened nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). Exposure to Ar activated nuclear receptors, including the pregnane-xenobiotic Panobinostat research buy receptor (PXR) and constitutive androstane receptor (CAR). To further characterize the role of these receptors in the development of NASH, we examined the effects of Ar exposure in diet-induced obese PXR and CAR knockout mice. Methods: C57Bl/6, PXR−/− and CAR−/− mice were exposed to Ar (20 mg/kg in corn oil via oral gavage)

and fed with HFD (42% kCal fat) for 12 weeks. Serum, liver and fat samples were taken for immunohistochemistry, RT-PCR, lipid analysis and adipocytokine Leukocyte receptor tyrosine kinase measurements. Results: HFD+Ar co-exposure resulted in decreased bodyweight gain and adi-pocyte size in CAR−/− mice vs. C57Bl/6 mice but no change was observed in PXR−/− mice. Using metabolic cages, CAR−/−mice exposed to Ar demonstrated increased movement and decreased food consumption. Both transgenic groups showed decreased respiration exchange rate but this was restored with Ar exposure. Histological examination of liver sections showed evidence of inflammation in all Ar-exposed mice. Both knockout models displayed

elevations in serum alanine transaminase activity when exposed to Ar, indicative of liver injury. Furthermore the knockout models also showed increased hepatic TNFα and IL-6 expression, with or without Ar-exposure vs. C57Bl/6 mice. IL-6 mRNA levels were highest in PXR−/−+Ar group. Ar exposure caused decreased serum insulin and consequently, no insulin resistance. However, PXR−/− mice exposed to Ar showed impaired glucose uptake and increased hepatic gluconeogenic PEPCK1 expression. PXR−/− mice also showed increased % fat composition, decreased lean tissue mass and increased liver to bodyweight ratio, irrespective of Ar exposure. Hepatic expression of lipogenic genes, including fatty acid synthase, sterol regulatory element binding protein-1 and CD36 were increased in PXR−/− mice exposed to Ar.

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