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LRH-1–dependent glucose sensing determines intermediary metabolism in liver
Maaike H. Oosterveer, … , Johan Auwerx, Kristina Schoonjans
Maaike H. Oosterveer, … , Johan Auwerx, Kristina Schoonjans
Published July 9, 2012
Citation Information: J Clin Invest. 2012;122(8):2817-2826. https://doi.org/10.1172/JCI62368.
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Research Article Metabolism

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

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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.

Authors

Maaike H. Oosterveer, Chikage Mataki, Hiroyasu Yamamoto, Taoufiq Harach, Norman Moullan, Theo H. van Dijk, Eduard Ayuso, Fatima Bosch, Catherine Postic, Albert K. Groen, Johan Auwerx, Kristina Schoonjans

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Figure 1

Reduced hepatic glucokinase and glycogen synthase fluxes in Alb-Cre;Lrh1fl/fl mice.

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Reduced hepatic glucokinase and glycogen synthase fluxes in Alb-Cre;Lrh1...
(A) Schematic representation of the model used for mass isotopomer distribution analysis. GP, glycogen phosphorylase; GS, glycogen synthase; G6Pase, glucose-6-phosphatase. (B–D) Glucose fluxes in Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) under normoglycemic (NG) and hyperglycemic (HG) conditions. (B) Glucokinase and (C) glucose-6-phosphatase flux and (D) glucose balance. (E–G) Glycogen fluxes in Alb-Cre;Lrh1fl/fl and Lrh1fl/fl mice under normoglycemic and hyperglycemic conditions. (E) Glycogen synthase and (F) glycogen phosphorylase flux and (G) glycogen balance. Data represent mean ± SEM for n = 5–9 per genotype. *P < 0.05 Alb-Cre;Lrh1fl/fl versus Lrh1fl/fl; #P < 0.05 hyperglycemic versus normoglycemic.
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