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.

Current Options and Future Directions for NAFLD and NASH Treatment

“…In addition, there are some other targets for NAFLD and NASH treatments, such as G protein-coupled receptors ( GPCRs ) [ 142 ], estrogen-related receptor alpha ( ERRα ) [ 143 ], bone morphogenetic proteins ( BMPs ) [ 144 ], and KLFs [ 24 , 145 ]. The treatment options for NAFLD/NASH are summarized in the graphic picture ( Figure 2 ).…”

Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies

“…They are transported across the gut epithelial barrier via monocarboxylate transporter 2 (MCT-1) and sodium-coupled MCT-1 [118,119] into portal blood to reach the liver and circulation. SCFAs are signaling molecules with differing receptor affinity for orphan G protein-coupled receptor 41 (GPR41) and GPR43, which are expressed on adipocytes, immune cells and enteroendocrine cells and the bone marrow, among others [116,120,121]. SCFAs thus decrease fat accumulation by modulating insulin sensitivity and enhancing energy expenditure in the liver and adipose tissue [122,123].…”

Molecular targets regulating endoplasmic reticulum-mitochondria crosstalk for NAFLD treatment

“…Gut microbiota-derived components and metabolites are involved in the pathogenesis of liver diseases [72]. Alteration of gut microbiota through bariatric surgery [73], such as sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB), has been shown to ameliorate hepatic inflammation, NAFLD, and NASH [74,75].…”