School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China.
Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Hepatology. 2020 Dec;72(6):1949-1967. doi: 10.1002/hep.31202. Epub 2020 Nov 6.
NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated.
Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte-specific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress.
In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.
NASH 是一种日益流行的疾病，是肝功能障碍的主要原因。先前的研究表明，脂肪酰基辅酶 A 二酰甘油脂肪酶 1（CRLS1）水平与胰岛素敏感性相关；然而，CRLS1 的精确作用及其在 NASH 病理过程中涉及 CRLS1 的潜在机制尚未阐明。
在这里，我们发现 CRLS1 在遗传肥胖和饮食诱导的小鼠模型中显著下调。体外研究表明，CRLS1 的过表达显著减轻肝细胞中的肝脂肪变性和炎症，而短发夹 RNA 介导的 CRLS1 敲低则加剧了这些异常。此外，肝细胞特异性 Crls1 敲除（Crls1-HKO）小鼠的高脂肪饮食诱导的胰岛素抵抗和肝脂肪变性明显加剧。值得注意的是，Crls1 耗竭显著加剧了 NASH 发展过程中高脂肪和高胆固醇饮食诱导的炎症反应和纤维化。RNA 测序分析系统地表明，脂质代谢紊乱明显加剧，其中炎症和纤维化是由于 Crls1 缺乏引起的。通过转录组分析，机制上鉴定出激活转录因子 3（ATF3）是 Crls1-HKO 小鼠中关键差异表达基因，我们的研究进一步表明，CRLS1 抑制 ATF3 的表达和活性在棕榈酸刺激的肝细胞中，而 ATF3 部分逆转了代谢应激下 CRLS1 过表达抑制的脂质积累和炎症。
总之，CRLS1 通过抑制 ATF3 的表达和活性，改善 NASH 病理过程中的胰岛素抵抗、肝脂肪变性、炎症和纤维化。
