| First Author | Chen CY | Year | 2021 |
| Journal | Am J Pathol | Volume | 191 |
| Issue | 7 | Pages | 1240-1254 |
| PubMed ID | 33894178 | Mgi Jnum | J:312305 |
| Mgi Id | MGI:6729795 | Doi | 10.1016/j.ajpath.2021.04.007 |
| Citation | Chen CY, et al. (2021) Inhibition of Estrogen-Related Receptor alpha Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis. Am J Pathol 191(7):1240-1254 |
| abstractText | 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 ERRalpha in lipid metabolism and the potential effect of inhibiting ERRalpha 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 ERRalpha was used to demonstrate that inhibiting ERRalpha blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERRalpha inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERRalpha-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERRalpha. In summary, these results establish ERRalpha as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRalpha as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRalpha. |
