Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A < sub > 2A < /sub > R improves hepatic and cardiac dysfunction of NASH mice

This study explores the effects of four-weeks A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of non-alcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR、AC、cAMP and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC、cAMP, PKA, HSL levels, decreased SREBP-1/FASN, MCP-1 and CD68 levels, reduces infiltrated CD11b+F4/80+ cells and adipogenesis in VAT of NASH+PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pre-treatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers, and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that, A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflamm...
Source: Am J Physiol Gastroi... - Category: Gastroenterology Authors: Source Type: research