Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice.

Abstract

BACKGROUND:

Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models.

METHODS:

We generated the miR-221/222flox/flox mice on a C57BL/6 J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl4) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models.

FINDINGS:

Hepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH.

INTERPRETATION:

Our findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang).

• Authors: Xiuli Jiang, Lei Jiang, Aijing Shan, Yutong Su, Yulong Cheng, Dalong Song, He Ji, Guang Ning, Weiqing Wang, Yanan Cao
• Journal: EBioMedicine (EBioMedicine) Vol. 37 Pg. 307-321 (Nov 2018) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30316865 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• MIRN221 microRNA, mouse
• MIRN222 microRNA, mouse
• MicroRNAs

Topics

• Adenoviridae
• Animals
• Cell Line
• Gene Targeting
• Genetic Vectors
• Lipid Metabolism (genetics)
• Liver (metabolism, pathology)
• Mice
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (genetics, metabolism, pathology, therapy)