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

Table 1 The role of G protein-coupled receptors in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and hepatocellular carcinoma

Liver disease	GPCRs	Expression	Ref.
NAFLD/Steatosis	GPR120	GPR120 agonist cpdA treatment increased insulin sensitivity and glucose tolerance and decreased hepatic steatosis in HFD-induced obese mice	[46]
HCC	GPR49	GPR49 is highly expressed in human HCC cell lines PLC/PRF/5 and HepG2; overexpression of GPR49 in HCC tissue with a mutation of beta-catenin exon 3 was also shown	[47]
HCC	GPR137	Knockdown of GPR137 in HepG2 cells induced cell cycle arrest and cell apoptosis. Additionally, low expression of GPR137 indicated the progression of human HCC and a low survival rate	[49]
NAFLD/Steatosis	GPR132	GPR132 was involved in hepatic lipid metabolism and gallstone formation in mice because GPR132-deficient mice fed a lithogenic diet quickly developed gallstones and had a high cholesterol saturation index	[51]
NAFLD/Steatosis	GPR55	GPR55-deficient (GPR55-/-) mice showed impaired insulin signaling and had a significant increase in total body fat and liver fatty acid synthase, resulting in the development of hepatic steatosis	[53]
NASH/Fibrosis	GPR91	Succinate in the fatty liver can activate HSC via GPR91 receptor, resulting in NASH progression	[45]
Liver injury/Fibrosis	GPBAR1	GPBAR1 is an upstream regulator of the axis expression of chemokine CCL2 and its receptor CCR2 in the interface of liver sinusoidal cells	[54]

GPCRs: G protein-coupled receptors; HCC: Hepatocellular carcinoma; HFD: High-fat diet; HSC: Hepatic stellate cell; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis.

Table 2 G protein-coupled receptor-mediated treatment in nonalcoholic fatty liver disease

GPCRs	Treatment	Study	Effect	Ref.
GPRC6A	Metabolitin, a peptide hormone	Mice	Specifically deleting Gprc6a in mouse hepatocytes caused hepatic fat accumulation. Metabolitin can significantly ameliorate NAFLD symptoms and inhibit gut triglyceride and cholesterol absorption and insulin resistance via GPRC6A-mediated activation of the 5’ AMP-activated protein kinase signaling pathway	[44,91]
GPR39	Agonist TC-G1008	Mice	Oral administration of TC-G1008 inhibited hepatic cell necrosis in concanavalin A-induced hepatitis liver in mice. In addition, acute administration of TC-G1008 reduced ethanol intake	[93,94]
GPR40	Agonist SCO-267	Mice	GPR40 deficiency was associated with hepatic inflammation and steatosis in low-fat diet-fed mice. Oral administration of SCO-267 reduced HFD-induced increase in liver weight, triglyceride and collagen production, and serum alanine aminotransferase	[95,96]
GPR40	Docosahexaenoic acid	Primary hepatocytes, HFD-fed mice	Treatment with DHA, an omega-3 fatty acid, inhibited lipid droplets by interacting with GPR40 in primary hepatocytes via reduced expression of lipogenic enzymes. In addition, it significantly reduced the HFD-induced liver steatosis score in mice	[99]
GPR43	Compound probiotics	Rats	Overexpressing GPR43 in adipose tissue kept mice lean on a HFD diet. Compound probiotics can modulate gut microbiota dysbiosis, SCFAs, and their receptors, like GPR43, in NAFLD rats	[30,102]
GPR84	Antagonist PBI-4547GPR84 Antagonists CpdA and CpdB	Gpr84-/- mice; Wild-type mice	PBI-4547 treatment ameliorated NAFLD-associated metabolic dysregulation, hepatic steatosis and ballooning, which was depleted in Gpr84-/- mice. Inhibition of GPR84 with antagonists CpdA and CpdB significantly reduced myeloid cell infiltration and ameliorated inflammation and fibrosis in acute liver injury	[100,101]
GPR120	TUG-891Agonist III	Hepatocytes; Mice	Agonist TUG-891 inhibited lipid accumulation in hepatocytes. Agonist III significantly suppressed macrophage infiltration, ROS production, hepatic inflammation, ER stress, and steatohepatitis	[97,98]

DHA: Docosahexaenoic acid; ER: endoplasmic reticulum; GPCRs: G protein-coupled receptors; HFD: High-fat diet; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; ROS: Reactive oxygen species; SCFA: Short-chain fatty acid.