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LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

ABSTRACT: Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect the liver against diet-induced steatosis and insulin resistance, little is known about how LRH-1 controls hepatic glucose and fatty acid metabolism under physiological conditions. We therefore assessed the role of LRH-1 in hepatic intermediary metabolism. In mice with conditional deletion of Lrh1 in liver, analysis of hepatic glucose fluxes revealed reduced glucokinase (GCK) and glycogen synthase fluxes as compared with those of wild-type littermates. These changes were attributed to direct transcriptional regulation of Gck by LRH-1. Impaired glucokinase-mediated glucose phosphorylation in LRH-1-deficient livers was also associated with reduced glycogen synthesis, glycolysis, and de novo lipogenesis in response to acute and prolonged glucose exposure. Accordingly, hepatic carbohydrate response element-binding protein activity was reduced in these animals. Cumulatively, these data identify LRH-1 as a key regulatory component of the hepatic glucose-sensing system required for proper integration of postprandial glucose and lipid metabolism.

SUBMITTER: Oosterveer MH

PROVIDER: S-EPMC3408738 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

Oosterveer Maaike H MH Mataki Chikage C Yamamoto Hiroyasu H Harach Taoufiq T Moullan Norman N van Dijk Theo H TH Ayuso Eduard E Bosch Fatima F Postic Catherine C Groen Albert K AK Auwerx Johan J Schoonjans Kristina K

The Journal of clinical investigation 20120709 8

Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect the liver against diet-induced steatosis and insulin resistance, little is known about how LRH-1 controls hepatic glucose and fatty acid metabolism under physiological conditions. We therefore assessed the role of LRH-1 in hepatic intermediary metabolism. In mice with conditional deletion of L ...[more]

PMID: 22772466

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LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

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LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

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