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摘要
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 (ERR alpha), 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 ERR alpha in mice demonstrated clear beneficial effects for loss of ERR alpha 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 ERR alpha-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, ERR alpha 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 ERR alpha 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 ERR alpha depended on the nutritional state, suggesting that negative modulation of ERR alpha activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.
- 出版日期2018-5
- 单位McGill
