Suppressing MASH fibrotic progression by blocking succinate-GPR91 signaling in hepatic stellate cells

Abstract

Background: The succinate receptor GPR91 is highly expressed in hepatic stellate cells (HSCs), with its expression further elevated during metabolic-dysfunction-associated steatohepatitis (MASH)-induced fibrotic progression. However, convincing in vivo data on whether blocking GPR91 signaling leads to fibrotic regression in MASH is lacking. Methods: MASH models were induced by choline-deficient amino acid-defined diet feeding along with lipopolysaccharide injection (CDAA-LPS) plus intraperitoneal injection of succinate or by high-fat and high-calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) in wild-type (WT) mice and HSC-specific GPR91 knockout (HSC-GPR91-KO) mice. Results: Administration of succinate significantly exacerbated fibrosis in CDAA-fed WT mice, as evidenced by increased collagen deposition and hydroxyproline levels along with an increased GPR91 expression in activated HSCs. Both WT and HSC-GPR91-KO mice exhibited substantial elevation in hepatic succinate levels upon HFCD-HF/G diet feeding. However, in comparison to HFCD+HF/G-fed WT mice, hepatic fibrosis was markedly ameliorated in HSC-GPR91-KO mice, as evidenced by diminished hepatic hydroxyproline content with downregulated fibrogenic markers. Succinate stimulation led to an increase in α-SMA, GPR91, phosphorylated ERK1/2, c-jun and Smad3 protein levels and enhanced the molecular interaction between c-jun and Smad3, inhibited forskolin-induced cAMP production in human HSCs, and increased p-NF-κB transcriptional activity, thereby suppressing HSC apoptosis. Conclusions: HSC-specific GPR91 receptor deficiency effectively halted hepatic fibrosis, probably through two distinct signaling pathways: suppressing the succinate-GPR91-Gβγ-ERK/c-jun-smad3 axis that positively regulates HSC activation; and abrogating the GPR91-Gαi-cAMP-NF-κB pathway that hinders their apoptosis. These findings confer GPR91 as a promising target for molecular interventions in blocking MASH-fibrotic progression.