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.
Mol Metab. 2021 Sep;51:101244. doi: 10.1016/j.molmet.2021.101244. Epub 2021 Apr 28.
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.
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.
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.
Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD.
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。
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。
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。
肝细胞 miR-34a 是 NAFLD 发展和进展的重要调节剂。miR-34a 可能是治疗 NAFLD 的有用靶点。
