Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China.
Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China.
Sci Rep. 2018 Mar 19;8(1):4809. doi: 10.1038/s41598-018-23141-8.
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.
肝细胞中甘油三酯的过度积累是肥胖相关非酒精性脂肪性肝病 (NAFLD) 的标志。肥胖症中饱和游离脂肪酸棕榈酸水平的升高是导致肝脏脂质过度积累的主要原因。核孤儿受体 Nur77 是一种转录调节剂和脂毒性传感器。本研究使用人 HepG2 肝癌细胞，旨在研究 Nur77 在棕榈酸诱导的肝脂肪变性中的功能作用。结果表明，棕榈酸显著诱导肝细胞中的脂质积累并抑制脂肪分解。此外，棕榈酸显著抑制 Nur77 的表达并刺激过氧化物酶体增殖物激活受体 γ (PPARγ) 的表达及其靶基因。Nur77 的过表达显著降低了棕榈酸诱导的 PPARγ 及其靶基因的表达。此外，Nur77 的过表达减轻了棕榈酸处理的肝细胞中的脂质积累并增强了脂肪分解。重要的是，G0S2 敲低显著减轻了棕榈酸处理的肝细胞中的脂质积累并增强了脂肪分解，而 G0S2 敲低对 Nur77、PPARγ 或其靶基因的棕榈酸诱导表达没有影响。总之，棕榈酸抑制 HepG2 细胞中 Nur77 的表达，而过表达 Nur77 通过下调 G0S2 减轻棕榈酸诱导的肝脂肪堆积。这些结果显示了 Nur77 调节的 G0S2 表达与棕榈酸诱导的肝脂肪变性之间的新分子机制。
