Ding Hao, Yu Jiang-Hong, Ge Ge, Ma Yan-Yun, Wang Jiu-Cun, Zhang Jun, Liu Jie
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
J Clin Transl Hepatol. 2023 Apr 28;11(2):261-272. doi: 10.14218/JCTH.2022.00042. Epub 2022 Jun 1.
RAS protein activator like 2 (RASAL2) is a newly discovered metabolic regulator involved in energy homeostasis and adipogenesis. However, whether RASAL2 is involved in hepatic lipid metabolism remains undetermined. This study explored the function of RASAL2 and elucidated its potential mechanisms in nonalcoholic fatty liver disease (NAFLD).
NAFLD models were established either by feeding mice a high-fat diet or by incubation of hepatocytes with 1 mM free fatty acids (oleic acid:palmitic acid=2:1). Pathological changes were observed by hematoxylin and eosin staining. Lipid accumulation was assessed by Oil Red O staining, BODIPY493/503 staining, and triglyceride quantification. The secretion rate of very low-density lipoprotein was determined by intravenous injection of tyloxapol. Gene regulation was analyzed by chromatin immunoprecipitation assays and hydroxymethylated DNA immunoprecipitation combined with real-time polymerase chain reaction.
RASAL2 deficiency ameliorated hepatic steatosis both and . Mechanistically, RASAL2 deficiency upregulated hepatic TET1 expression by activating the AKT signaling pathway and thereby promoted MTTP expression by DNA hydroxymethylation, leading to increased production and secretion of very low-density lipoprotein, which is the major carrier of triglycerides exported from the liver to distal tissues.
Our study reports the first evidence that RASAL2 deficiency ameliorates hepatic steatosis by regulating lipid metabolism through the AKT/TET1/MTTP axis. These findings will help understand the pathogenesis of NAFLD and highlight the potency of RASAL2 as a new molecular target for NAFLD.
RAS蛋白激活剂样2（RASAL2）是一种新发现的参与能量稳态和脂肪生成的代谢调节因子。然而，RASAL2是否参与肝脏脂质代谢仍未确定。本研究探讨了RASAL2的功能，并阐明了其在非酒精性脂肪性肝病（NAFLD）中的潜在机制。
通过给小鼠喂食高脂饮食或用1 mM游离脂肪酸（油酸：棕榈酸 = 2:1）孵育肝细胞建立NAFLD模型。通过苏木精和伊红染色观察病理变化。通过油红O染色、BODIPY493/503染色和甘油三酯定量评估脂质积累。通过静脉注射泰洛沙泊测定极低密度脂蛋白的分泌率。通过染色质免疫沉淀试验和羟甲基化DNA免疫沉淀结合实时聚合酶链反应分析基因调控。
RASAL2缺陷在[具体情况1]和[具体情况2]中均改善了肝脏脂肪变性。机制上，RASAL2缺陷通过激活AKT信号通路上调肝脏TET1表达，从而通过DNA羟甲基化促进MTTP表达，导致极低密度脂蛋白的产生和分泌增加，极低密度脂蛋白是从肝脏输出到远端组织的甘油三酯的主要载体。
我们的研究首次报道了RASAL2缺陷通过AKT/TET1/MTTP轴调节脂质代谢改善肝脏脂肪变性的证据。这些发现将有助于理解NAFLD的发病机制，并突出RASAL2作为NAFLD新分子靶点的潜力。
