Kim Kwang-Youn, Jang Hyun-Jun, Yang Yong Ryoul, Park Kwang-Il, Seo JeongKon, Shin Il-Woo, Jeon Tae-Il, Ahn Soon-Cheol, Suh Pann-Ghill, Osborne Timothy F, Seo Young-Kyo
School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Cheomdan-ro 70, Daegu 41062, Korea.
Sci Rep. 2016 Oct 21;6:35732. doi: 10.1038/srep35732.
Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.
自噬失调与脂肪变性及非酒精性脂肪性肝病（NAFLD）相关，但二者之间的联系机制仍知之甚少。在此，我们发现，在高脂饮食（HFD）喂养的小鼠中，联合使用洛伐他汀和依泽替米贝（L/E）可显著逆转肝脏甘油三酯蓄积，同时伴随SREBP-2驱动的自噬增加。我们进一步表明，他汀类药物介导的SREBP-2增加直接激活含patatin样磷脂酶结构域的酶8（PNPLA8）基因的表达，并且PNPLA8与自噬体相关联，并与细胞内甘油三酯的减少有关。此外，我们表明，PNPLA8的过表达通过增加HFD喂养小鼠肝细胞中的自噬，显著降低肝脏脂肪变性。活细胞成像分析还显示，PNPLA8与LC3动态相互作用，我们认为SREBP-2/PNPLA8轴代表了脂质稳态的一种新型调节机制。这些数据为他汀类药物对降低NAFLD患者肝脏甘油三酯水平的有益作用提供了一种可能的机制。
