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

Nature Communications
Hongjiao XuXianxing Jiang

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.

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Citations

Apr 20, 2021·European Journal of Internal Medicine·Agostino Di CiaulaPiero Portincasa
May 1, 2021·International Journal of Molecular Sciences·Yoshitaka SakuraiTakashi Kadowaki
Jun 3, 2021·International Journal of Molecular Sciences·Ersilia NigroLuigi Sapio
Jul 3, 2021·International Journal of Molecular Sciences·Siarhei A DabravolskiAlexander N Orekhov

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
RNAseq
transfection
electrophoresis
confocal microscopy

Software Mentioned

RNAseq
MOE
ImageJ
Discovery Studio ( DS )
Tanon
Phoenix WinNonlin
Molecular Operating Environment ( MOE )
GraphPad Prism
Image

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