Divergent Role of Estrogen-Related Receptor α in Lipid- and Fasting-Induced Hepatic Steatosis in Mice

Abstract

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 α (ERRα), 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 ERRα in mice demonstrated clear beneficial effects for loss of ERRα 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 ERRα-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, ERRα 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 ERRα 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 ERRα depended on the nutritional state, suggesting that negative modulation of ERRα activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.

Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development

“…All three of these aspects are believed to contribute to NAFLD with the contribution of each of these aspects varying under different physiological conditions. However, global ERRα knockout mice did not display NAFLD compared to our ERRαLKO mice 43 , 53 , 54 . This discrepancy is likely due to reduced nutrient absorption in global ERRα knockout mice.…”

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

“…Chaveroux et al showed that the genetic and pharmacological inhibition of ESRRA activity exacerbated hepatosteatosis in rapamycin-treated mice [61]. In contrast, B'Chir et al showed that the genetic ablation of ESRRA protected against fatty liver induced in DIO [93]. Consistent with the findings in ESRRA null mice, ESRRA inverse agonists, compound 29 (C29) and compound 50 (C50), also show obesity resistance in DIO mouse models [94][95][96].…”

ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease

“…Moreover, the molecular clock serves as another input signal modulating ERRα levels in a circadian manner in tissues including liver and WAT (84–87). Furthermore, ERRα adapts to nutritional challenges such as increased intake of a lipid-rich diet or cycles of nutrient deprivation and availability by modulating metabolic gene and metabolite levels (88, 89). Rapamycin treatment, which is known to mimic amino-acid-like starvation, as well as glucose and amino acids deprivation also affect ERRα protein stability and transcriptional networks (23).…”

“…Genetic or pharmacological manipulation of ERRα in rodent and cell-based studies have further characterized the genes and biological programs regulated by ERRα, establishing a major role of ERRα in liver homeostasis. A list of currently known genes found either activated or repressed by ERRα in hepatocytes in a context-specific manner with evidence for direct binding of ERRα within ± 20 kb of the TSS from ChIP-based studies is summarized in Table S1 (22, 23, 82, 84, 88, 90, 95–103). A schematic of these direct ERRα-regulated genes associated to general biological processes are shown in Figure 2.…”