RGD Reference Report - Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice. - Rat Genome Database

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

Authors: Jiang, Xiuli  Jiang, Lei  Shan, Aijing  Su, Yutong  Cheng, Yulong  Song, Dalong  Ji, He  Ning, Guang  Wang, Weiqing  Cao, Yanan 
Citation: Jiang X, etal., EBioMedicine. 2018 Nov;37:307-321. doi: 10.1016/j.ebiom.2018.09.051. Epub 2018 Oct 10.
RGD ID: 18337274
Pubmed: PMID:30316865   (View Abstract at PubMed)
PMCID: PMC6284352   (View Article at PubMed Central)
DOI: DOI:10.1016/j.ebiom.2018.09.051   (Journal Full-text)


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).



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MIR221Humanmetabolic dysfunction-associated steatohepatitis treatmentISOMir221 (Mus musculus) RGD 
Mir221Mousemetabolic dysfunction-associated steatohepatitis treatmentIMP  RGD 
Mir221Ratmetabolic dysfunction-associated steatohepatitis treatmentISOMir221 (Mus musculus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mir221  (microRNA 221)

Genes (Mus musculus)
Mir221  (microRNA 221)

Genes (Homo sapiens)
MIR221  (microRNA 221)


Additional Information