title: Hsp90 modulates PPARγ activity in a mouse model of nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent complication of obesity, yet cellular mechanisms that lead to its development are not well defined. Previously, we have documented hepatic steatosis in mice carrying a mutation in the Sec61a1 gene. Here we examined the mechanism behind NAFLD in Sec61a1 mutant mice. Livers of mutant mice exhibited upregulation of Pparg and its target genes Cd36, Cidec, and Lpl, correlating with increased uptake of fatty acid. Interestingly, these mice also displayed activation of the heat shock response (HSR), with elevated levels of heat shock protein (Hsp) 70, Hsp90, and heat shock factor 1. In cell lines, inhibition of Hsp90 function reduced Pparγ signaling and protein levels. Conversely, overexpression of Hsp90 increased Pparγ signaling and protein levels by reducing degradation. This may occur via a physical interaction as Hsp90 and Pparγ coimmunoprecipitated in vivo. Furthermore, inhibition of Hsp90 in Sec61a1 mutant hepatocytes also reduced Pparγ protein levels and signaling. Finally, overexpression of Hsp90 in liver cell lines increased neutral lipid accumulation, and this accumulation was blocked by Hsp90 inhibition. Our results show that the HSR and Hsp90 play an important role in the development of NAFLD, opening new avenues for the prevention and treatment of this highly prevalent disease.
authors.affiliation: Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wheeler
authors.affiliation: Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gekakis
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000069816:SEC Translocation Channels / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047495:PPAR gamma; D000069816:SEC Translocation Channels; C577653:SEC61A1 protein, mouse
keywords: heat shock protein 90; heat shock response; peroxisome proliferator-activated receptor γ; steatosis