甾醇调节元件结合蛋白(SREBPs)介导的新生脂肪生成增强被认为与非酒精性脂肪性肝炎(NASH)发病机制有关。本研究在小鼠模型中评估SREBP抑制对NASH和肝癌发展的影响。

在肝脏中通过缺失SREBP裂解激活蛋白(SCAP)而抑制SREBP，虽然显著减少肝脏脂肪变性，但却加剧肝损伤、纤维化和癌变。这些表型可通过恢复SREBP功能得到改善。转录组和脂质组分析显示，SCAP/SREBP途径抑制磷脂酰胆碱脂肪酸(FA)的合成受损，并通过溶血磷脂酰胆碱酰基转移酶3 (LPCAT3)下调，扰乱脂肪酸与磷脂酰胆碱的结合，从而导致内质网(ER)应激和肝细胞损伤。补充磷脂酰胆碱可显著改善SCAP缺失引起的肝损伤和内质网应激。在人类NASH中，SCAP/ SREBP/LPCAT3轴的活性与肝纤维化严重程度呈负相关。SREBP抑制也与自噬受损共同触发肝损伤。

Abstract

Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

原文链接

https://pubmed.ncbi.nlm.nih.gov/35380992/

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