Abstract
Excessive triglyceride accumulation in hepatocytes is the hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). Elevated levels of the saturated free fatty acid palmitate in obesity are a major contributor to excessive hepatic lipid accumulation. The nuclear orphan receptor Nur77 is a transcriptional regulator and a lipotoxicity sensor. Using human HepG2 hepatoma cells, this study aimed to investigate the functional role of Nur77 in palmitate-induced hepatic steatosis. The results revealed that palmitate significantly induced lipid accumulation and suppressed lipolysis in hepatocytes. In addition, palmitate significantly suppressed Nur77 expression and stimulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes. Nur77 overexpression significantly reduced palmitate-induced expression of PPARγ and its target genes. Moreover, Nur77 overexpression attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes. Importantly, G0S2 knockdown significantly attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes, whereas G0S2 knockdown had no effect on the palmitate-induced expression of Nur77, PPARγ, or PPARγ target genes. In summary, palmitate suppresses Nur77 expression in HepG2 cells, and Nur77 overexpression alleviates palmitate-induced hepatic fat accumulation by down-regulating G0S2. These results display a novel molecular mechanism linking Nur77-regulated G0S2 expression to palmitate-induced hepatic steatosis.
Highlights
A decreased rate of triglyceride mobilization plays a key role in triglyceride accumulation in the liver[11,12]
HepG2 cells were incubated with increasing concentrations of palmitate for 24 h, and a quantitative PCR analysis revealed that palmitate induced a dose-dependent decrease in Nur[77] mRNA expression and a dose-dependent increase in the mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes (G0S2, G protein-coupled receptor 81 (GPR81), G protein-coupled receptor 109A (GPR109A), and Adipoq) (Fig. 2A)
G0S2, GPR81, GPR109A, and Adipoq are known downstream target genes of PPARγ that are involved in lipolysis under distinct physiological conditions[25,36]
Summary
A decreased rate of triglyceride mobilization plays a key role in triglyceride accumulation in the liver[11,12]. Further chromatin immunoprecipitation and luciferase assays have shown that Nur[77] directly binds to and represses the PPARγ promoter and reduces the expression of PPARγ and PPARγ-regulated downstream target genes[25]. These findings demonstrate that Nur[77] is a direct repressor of PPARγ expression. Based on these observations, we made the following hypothesis: (1) palmitate suppresses Nur[77] and subsequently stimulates the expression of its downstream target PPARγ and G0S2, (2) this increase in G0S2 expression contributes to palmitate-induced fat accumulation in the liver, and (3) Nur[77] overexpression suppresses G0S2 expression in the liver, thereby exerting a protective effect against palmitate-induced hepatic steatosis. Our results provide novel information regarding the molecular mechanism through which palmitate induces fat accumulation in hepatocytes
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