Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis

The estrogen-related receptor (ERR) family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study was to explore the role of ERR alpha in lipid metabolism and the potential effect of inhibiting ERR alpha on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, three experimental mouse models: high-fat diet, high-carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/ phosphatidylinositol 3-kinase signaling pathway, were used. A recently developed small-molecule inhibitor for ERR alpha was used to demonstrate that inhibiting ERR alpha blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERR alpha inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERR alpha-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERR alpha. In summary, these results establish ERR alpha as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERR alpha as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERR alpha.

Automated summary

Inhibiting ERR alpha can block the development of NAFLD, reduce lipid accumulation, and attenuate NASH. Glycerolipid synthesis was identified as an additional mechanism for ERR alpha-regulated NAFLD/NASH development, with glycerophosphate acyltransferase 4 identified as a novel transcriptional target of ERR alpha. These results establish ERR alpha as a potential target for NAFLD/NASH treatment and highlight novel signaling pathways regulated by ERR alpha.