Jung Tae Woo, Hong Ho Cheol, Hwang Hwan-Jin, Yoo Hye Jin, Baik Sei Hyun, Choi Kyung Mook
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Mol Cell Endocrinol. 2015 Dec 5;417:131-40. doi: 10.1016/j.mce.2015.09.027. Epub 2015 Sep 28.
C1q/TNF-Related Protein (CTRP) 9, the closest paralog of adiponectin, has been reported to protect against diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. We explored the protective effect of CTRP9 against hepatic steatosis and apoptosis, and identified the mechanisms through autophagy and endoplasmic reticulum (ER) stress using in vitro and in vivo experiments. Treating HepG2 cells with human recombinant CTRP9 significantly ameliorated palmitate- or tunicamycin-induced dysregulation of lipid metabolism, caspase 3 activity and chromatin condensation, which lead to reduction of hepatic triglyceride (TG) accumulation. CTRP9 treatment induced autophagy markers including LC3 conversion, P62 degradation, Beclin1 and ATG7 through AMPK phosphorylation in human primary hepatocytes. Furthermore, CTRP9 decreased palmitate- or tunicamycin-induced ER stress markers, such as eIF2α, CHOP and IRE-1, in HepG2 cells. Compound C, an AMPK inhibitor, and 3 methyladenine (3 MA), an autophagy inhibitor, canceled the effects of CTRP9 on ER stress, apoptosis and hepatic steatosis. In the livers of HFD-fed mice, adenovirus-mediated CTRP9 overexpression significantly induced AMPK phosphorylation and autophagy, whereas suppressed ER stress markers. In addition, both SREBP1-mediated lipogenic gene expression and apoptosis were significantly attenuated, which result in improvement in hepatic steatosis by overexpression of CTRP9. These results demonstrate that CTRP9 alleviates hepatic steatosis through relief of ER stress via the AMPK-mediated induction of autophagy.
C1q/TNF相关蛋白（CTRP）9是脂联素最接近的旁系同源物，据报道它能预防饮食诱导的肥胖和非酒精性脂肪性肝病（NAFLD）。然而，其潜在机制尚未完全阐明。我们通过体外和体内实验，探讨了CTRP9对肝脂肪变性和细胞凋亡的保护作用，并确定了自噬和内质网（ER）应激的机制。用人重组CTRP9处理HepG2细胞可显著改善棕榈酸或衣霉素诱导的脂质代谢失调、半胱天冬酶3活性和染色质凝聚，从而减少肝甘油三酯（TG）积累。CTRP9处理通过人原代肝细胞中的AMPK磷酸化诱导自噬标志物，包括LC3转化、P62降解、Beclin1和ATG7。此外，CTRP9降低了HepG2细胞中棕榈酸或衣霉素诱导的ER应激标志物，如eIF2α、CHOP和IRE-1。AMPK抑制剂Compound C和自噬抑制剂3-甲基腺嘌呤（3MA）消除了CTRP9对ER应激、细胞凋亡和肝脂肪变性的影响。在高脂饮食喂养小鼠的肝脏中，腺病毒介导的CTRP9过表达显著诱导AMPK磷酸化和自噬，同时抑制ER应激标志物。此外，SREBP1介导的脂肪生成基因表达和细胞凋亡均显著减弱，CTRP9过表达改善了肝脂肪变性。这些结果表明，CTRP9通过AMPK介导的自噬诱导减轻ER应激，从而减轻肝脂肪变性。
