Am J Physiol Gastrointest Liver Physiol. 2024 Jan 22. doi: 10.1152/ajpgi.00104.2023. Online ahead of print.

ABSTRACT

A_2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP and protein kinase A (PKA) formation through A_2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of four-weeks A_2AR 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 A_2AR、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, A_2AR agonist pre-treatment-related normalization of A_2AR-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, A_2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypo-contractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.

PMID:38252682 | DOI:10.1152/ajpgi.00104.2023