肝细胞 miR-34a 是非酒精性脂肪性肝病发生发展的关键调节因子。

Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.

机构信息

Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.

Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

出版信息

Mol Metab. 2021 Sep;51:101244. doi: 10.1016/j.molmet.2021.101244. Epub 2021 Apr 28.

DOI:10.1016/j.molmet.2021.101244

PMID:33930596

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8141777/

Abstract

OBJECTIVE

Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice and patients with non-alcoholic steatohepatitis (NASH), yet hepatocyte miR-34a's role in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.

METHODS

Mice overexpressing or deficient in hepatocyte miR-34a and control mice were fed a diet enriched in fats, cholesterol, and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression, and reversal of NAFLD was determined.

RESULTS

The hepatocyte-specific expression of miR-34a aggravated HFCF diet-induced NAFLD. In contrast, germline or adult-onset deletion of hepatocyte miR-34a attenuated the development and progression of NAFLD. In addition, pharmacological inhibition of miR-34a reversed HFCF diet-induced steatohepatitis. Mechanistically, hepatocyte miR-34a regulated the development and progression of NAFLD by inducing lipid absorption, lipogenesis, inflammation, and apoptosis but inhibiting fatty acid oxidation.

CONCLUSIONS

Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD.

摘要

目的

在饮食诱导或遗传肥胖的小鼠和非酒精性脂肪性肝炎（NASH）患者中，肝 miR-34a 的表达升高，但肝细胞 miR-34a 在非酒精性脂肪性肝病（NAFLD）从非酒精性脂肪肝（NAFL）进展为 NASH 中的作用仍有待阐明。

方法

过表达或缺乏肝细胞 miR-34a 的小鼠和对照小鼠喂食富含脂肪、胆固醇和果糖的饮食（HFCF）以诱导 NASH。用 miR-34a 抑制剂或 scramble 对照寡核苷酸处理具有 NASH 的 C57BL/6 小鼠。确定 miR-34a 对 NAFLD 的发展、进展和逆转的影响。

结果

肝细胞特异性表达 miR-34a 加重了 HFCF 饮食诱导的 NAFLD。相比之下，肝细胞 miR-34a 的种系或成年期缺失减弱了 NAFLD 的发展和进展。此外，药理抑制 miR-34a 逆转了 HFCF 饮食诱导的脂肪性肝炎。机制上，肝细胞 miR-34a 通过诱导脂质吸收、脂肪生成、炎症和细胞凋亡但抑制脂肪酸氧化来调节 NAFLD 的发展和进展。