AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis

Hongjiao Xu, Qian Zhao, Nazi Song, Zhibin Yan, Runfeng Lin, Shuohan Wu, Lili Jiang, Sihua Hong, Junqiu Xie, Huihao Zhou, Rui Wang and Xianxing Jiang ()
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Hongjiao Xu: Sun Yat-Sen University
Qian Zhao: Sun Yat-Sen University
Nazi Song: Sun Yat-Sen University
Zhibin Yan: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University
Runfeng Lin: Sun Yat-Sen University
Shuohan Wu: Sun Yat-Sen University
Lili Jiang: Sun Yat-Sen University
Sihua Hong: Sun Yat-Sen University
Junqiu Xie: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University
Huihao Zhou: Sun Yat-Sen University
Rui Wang: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University
Xianxing Jiang: Sun Yat-Sen University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.

Date: 2020
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DOI: 10.1038/s41467-020-19668-y

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