Zhang Xiao, Zhang Puhong, Gao Jialin, Huang Qiang
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.
Department of Clinical Laboratory, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China.
Biochem Biophys Res Commun. 2018 Jan 22;495(4):2643-2648. doi: 10.1016/j.bbrc.2017.12.148. Epub 2017 Dec 27.
Autophagy is thought to be a key mechanism in maintaining the balance of liver lipid metabolism. However, the relationship between apolipoprotein M (ApoM) and autophagy has not been reported, and the role of ApoM in triglyceride metabolism is still unclear. In this study, we investigated the correlation between ApoM and autophagy and liver triglyceride metabolism in ApoM-knockout animal and cellular models. First, we observed that spontaneous hepatic steatosis developed in the liver of adult ApoM mice, which was presented as the accumulation of large quantities of lipid droplets in hepatocytes under electron microscopy; Oil Red O staining showed significant accumulation of triglycerides. At the molecular level, the expression of lipid synthesis-associated proteins (primarily triglyceride synthesis) as well as acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBP1) was upregulated. Moreover, lipid metabolic disorder and accumulation were accompanied by dysfunction in autophagy, which displayed predominantly as inhibition of the degradation pathway; for example, P62 protein accumulated and key proteins involved in the initiation of autophagy including ATG7, ATG5-12, Beclin1 and the LC3BII/LC3BI ratio were upregulated as a feedback response. When the autophagy dysfunction was ameliorated by the activation of autophagy pathways induced by starvation, the lipid metabolic disorder was corrected to a certain extent. This suggests that the autophagy dysfunction caused by the deficiency of ApoM is an important factor in hepatic steatosis (triglyceride accumulation). ApoM plays a key role in normal autophagy activity in the liver and thereby further regulates the metabolism of liver lipids, particularly triglycerides.
自噬被认为是维持肝脏脂质代谢平衡的关键机制。然而，载脂蛋白M（ApoM）与自噬之间的关系尚未见报道，且ApoM在甘油三酯代谢中的作用仍不清楚。在本研究中，我们在ApoM基因敲除动物和细胞模型中研究了ApoM与自噬以及肝脏甘油三酯代谢之间的相关性。首先，我们观察到成年ApoM基因敲除小鼠肝脏出现自发性肝脂肪变性，在电子显微镜下表现为肝细胞内大量脂滴积聚；油红O染色显示甘油三酯显著积聚。在分子水平上，脂质合成相关蛋白（主要是甘油三酯合成）以及乙酰辅酶A羧化酶α（ACACA）、脂肪酸合酶（FASN）和固醇调节元件结合蛋白1（SREBP1）的表达上调。此外，脂质代谢紊乱和积聚伴随着自噬功能障碍，主要表现为降解途径受到抑制；例如，P62蛋白积聚，自噬起始相关的关键蛋白包括ATG7、ATG5-12、Beclin1以及LC3BII/LC3BI比值上调作为反馈反应。当通过饥饿诱导的自噬途径激活改善自噬功能障碍时，脂质代谢紊乱在一定程度上得到纠正。这表明ApoM缺乏导致的自噬功能障碍是肝脂肪变性（甘油三酯积聚）的一个重要因素。ApoM在肝脏正常自噬活性中起关键作用，从而进一步调节肝脏脂质代谢，尤其是甘油三酯代谢。
