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

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.

• Authors: Yanyong Xu, Yingdong Zhu, Shuwei Hu, Xiaoli Pan, Fathima Cassim Bawa, Helen H Wang, David Q-H Wang, Liya Yin, Yanqiao Zhang
• Journal: Molecular metabolism (Mol Metab) Vol. 51 Pg. 101244 (09 2021) ISSN: 2212-8778 [Electronic] Germany
• PMID: 33930596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Chemical References

• MIRN34a microRNA, mouse
• MicroRNAs
• Fructose
• Cholesterol

Topics

• Animals
• Apoptosis (genetics)
• Cholesterol (administration & dosage, adverse effects)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Disease Progression
• Exosomes (metabolism)
• Fructose (administration & dosage, adverse effects)
• Gene Expression Regulation (drug effects)
• Hepatocytes (cytology, drug effects, metabolism)
• Humans
• Lipogenesis (drug effects, genetics)
• Liver (cytology, pathology)
• Male
• Mice
• Mice, Transgenic
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (drug therapy, genetics, pathology)