| First Author | B'chir W | Year | 2018 |
| Journal | Endocrinology | Volume | 159 |
| Issue | 5 | Pages | 2153-2164 |
| PubMed ID | 29635284 | Mgi Jnum | J:261713 |
| Mgi Id | MGI:6155295 | Doi | 10.1210/en.2018-00115 |
| Citation | B'chir W, et al. (2018) Divergent Role of Estrogen-Related Receptor alpha in Lipid- and Fasting-Induced Hepatic Steatosis in Mice. Endocrinology 159(5):2153-2164 |
| abstractText | Given the increasing prevalence of obesity and the metabolic syndrome, identification of intrinsic molecular programs responsible for ensuring fuel homeostasis and preventing metabolic disease is needed. We investigated whether the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), a major regulator of energy metabolism, plays a role in lipid homeostasis and the development of nonalcoholic fatty liver disease (NAFLD) in response to chronic high-fat diet (HFD) consumption and long-term fasting. Systemic ablation of ERRalpha in mice demonstrated clear beneficial effects for loss of ERRalpha function in protection from HFD-provoked body weight gain manifested not only from a reduction in white adipose tissue stores but also from an impediment in intrahepatic lipid accumulation. The prevention of HFD-induced NAFLD in ERRalpha-null mice was underscored by transcriptional repression of de novo lipogenesis, which was upregulated in wild-type mice, a known contributing factor to lipid-stimulated hepatic steatosis. Surprisingly, given these findings, ERRalpha deficiency had no significant impact on the degree of fasting-induced NAFLD, involving the mobilization of adipocyte triglyceride (TG) stores into the liver. However, the presence of ERRalpha was essential for acute refeeding-mediated reversal of fasting-induced hepatic TG accretion, underpinned by impaired downregulation of adipose TG lipolysis and reduced hepatic mitochondrial oxidative activity. Taken together, the regulation of lipid handling by ERRalpha depended on the nutritional state, suggesting that negative modulation of ERRalpha activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease. |
