G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.

Keywords: Nonalcoholic fatty liver disease; G protein-coupled receptors; Metabolism; Bile acids; Short-chain fatty acids; Gut microbiota

Core Tip: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Without effective treatment, NAFLD can progress to fibrosis, cirrhosis, and liver cancer. Currently, there is no effective treatment option. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD, through their function as receptors for bile acids and free fatty acids. Therapies such as probiotics and GPCR agonists could be applied to modulate GPCR function to ameliorate liver metabolism syndrome. Herein, this review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD.