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. IntroductionThe liver plays a central role in metabolic homeostasis by coordinating the synthesis, storage, breakdown, and redistribution of nutrients. Adequate control of these metabolic processes is of importance to accommodate systemic fuel requirements and availability. This is achieved through regulatory complexes that modulate both the catalytic activity and the expression level of metabolic enzymes. While the first usually enables rapid changes in enzymatic activity triggered by allosteric regulation or covalent modification, the second regulatory process is slower and involves transcription factors that adjust gene expression levels. In this context, nuclear receptors and their coregulators have been shown to play a key role in the transcriptional regulation of metabolic enzyme expression in response to changes in cellular nutrient and energy status (1, 2).Liver receptor homolog 1 (LRH-1, also known as NR5A2), a member of the NR5A superfamily of nuclear receptors, is highly expressed in the liver. Hepatic LRH-1 promotes the expression of the bile acid-synthesizing enzymes Cyp7a1 and Cyp8b1 (3-5), while it suppresses acute phase response genes (6, 7). As a consequence, bile acid metabolism is altered in liver-specific LRH-1 knockout mice (3, 4), and LRH-1 heterozygous animals show an exacerbated inflammatory response (6). Other established LRH-1 target genes in the liver are known mediators of hepatic cholesterol uptake and efflux (8, 9), HDL formation (10, 11), cholesterol exchange between lipoproteins (12), and fatty acid synthesis (13). Although these findings point to a broader role for LRH-1 in hepatic lipid metabolism and reverse cholesterol transport, their physiological impact is as yet unknown.

E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis

“…Glycolysis experiments were performed as previously described (40). Briefly, hepatocytes were seeded onto Seahorse XF24 plates (Seahorse Bioscience) and then glucose starved overnight.…”

Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

“…LRH-1 was first discovered in mouse liver as a transcription factor that regulates the transcription of α-fetoprotein (Becker-Andre et al, 1993;Galarneau et al, 1996). LRH-1 functions in the control of glycolysis as well as cholesterol and bile acid homeostasis by regulating the transcription of various genes, such as glucokinase (Oosterveer et al, 2012), SR-BI (Schoonjans et al, 2002), CYP7A1, and CYP8B1 (Goodwin et al, 2000;Lu et al, 2000). In addition to liver, LRH-1 is highly expressed in tissues of endodermal origin (pancreas and intestine), and involved in metabolism, inflammation, and stem cell renewal (Benod et al, 2011;Botrugno et al, 2004;Coste et al, 2007;Fayard et al, 2003;Fernandez-Marcos et al, 2011;Lazarus et al, 2012).…”

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

“…In the liver, LRH-1 is an important regulator of glucose, cholesterol, and bile acid metabolism (5). Liver-specific Lrh-1 knockout mice display reduced glycolytic flux and de novo lipogenesis secondary to impaired glucokinase activity (6). On the other hand, treatment of mice with the LRH-1 agonist 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) protects animals from developing NAFLD and insulin resistance in genetic and dietary models of diabesity (7,8).…”