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MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH

2022; Cell Press; Volume: 34; Issue: 7 Linguagem: Inglês

10.1016/j.cmet.2022.05.008

1932-7420

Hong Gao, Zhongmou Jin, Gautam Bandyopadhyay, Karina Cunha e Rocha, Xiao Liu, Huayi Zhao, Dinghong Zhang, Hani Jouihan, Soheil Pourshahian, Tatiana Kisseleva, David A. Brenner, Wei Ying, Jerrold M. Olefsky,

Cancer-related molecular mechanisms research

Summary Nonalcoholic steatohepatitis (NASH) is a liver disease associated with significant morbidity. Kupffer cells (KCs) produce endogenous miR-690 and, via exosome secretion, shuttle this miRNA to other liver cells, such as hepatocytes, recruited hepatic macrophages (RHMs), and hepatic stellate cells (HSCs). miR-690 directly inhibits fibrogenesis in HSCs, inflammation in RHMs, and de novo lipogenesis in hepatocytes. When an miR-690 mimic is administered to NASH mice in vivo , all the features of the NASH phenotype are robustly inhibited. During the development of NASH, KCs become miR-690 deficient, and miR-690 levels are markedly lower in mouse and human NASH livers than in controls. KC-specific KO of miR-690 promotes NASH pathogenesis. A primary target of miR-690 is NADK mRNA, and NADK levels are inversely proportional to the cellular miR-690 content. These studies show that KCs play a central role in the etiology of NASH and raise the possibility that miR-690 could emerge as a therapeutic for this condition.