Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation
Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation
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DOI：
10.1002/hep.31202
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发表时间：
2020-11-06
期刊：
影响因子：
13.5
通讯作者：
Mei, Zhinan
中科院分区：
文献类型：
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作者：
Tu, Chuyue;Xiong, Hui;Mei, Zhinan
背景和目的NASH是一种日益流行的疾病，是肝功能障碍的主要原因。以往的研究表明，脂肪心磷脂合成酶1（CRLS 1）水平与胰岛素敏感性，然而，CRLS 1的确切作用和潜在的机制，涉及CRLS 1在NASH.Approach和结果病理过程中尚未阐明在这里，我们发现，CRLS 1是显着下调在遗传性肥胖和饮食诱导的小鼠模型。体外研究表明，CRLS 1的过表达显著减弱了肝细胞中的肝脂肪变性和炎症，而短发夹RNA介导的CRLS 1敲低则加重了这些异常。此外，在肝细胞特异性Crls 1基因敲除（Crls 1-HKO）小鼠中，高脂饮食诱导的胰岛素抵抗和肝脏脂肪变性显著加重。值得注意的是，在NASH发展过程中，Crls 1缺失显著加重了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，显着恶化的脂质代谢紊乱，炎症和纤维化导致Crls 1缺陷。在机制上，通过转录组学分析确定了激活转录因子3（ATF 3）是Crls 1-HKO小鼠中关键的差异表达基因，并且我们的研究进一步表明，在棕榈酸刺激的肝细胞中，CRLS 1抑制ATF 3的表达并抑制其活性，而ATF 3部分逆转代谢应激下CRLS 1过表达抑制的脂质积累和炎症。CRLS 1通过抑制ATF 3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。
Background and Aims 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.Approach and Results 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.Conclusions 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.