Effects of G protein-coupled receptors in common liver diseases

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Post by Master, Doctor Mai Vien Phuong - Gastrointestinal endoscopist - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital

The G protein-coupled receptor is associated with distinct G protein families, including Gs, Gi, and Gq. Heterotrimeric G proteins are involved in the signaling of about 800 members of the G protein-coupled receptor. Some of these signaling pathways play an important role in liver metabolism.

1. The role of some G protein-coupled receptors in liver diseases

To date, several G protein-coupled receptors have been shown to play an important role in common liver diseases. Several important G protein-coupled receptors have potential clinical value at various stages of liver disease, from NAFLD to HCC. For example, GPR120 is a functional receptor for ω-3 fatty acids with potent anti-inflammatory and insulin resistance effects. The role of G protein-coupled receptors in common liver diseases is as follows:

Abbreviation: HCC: Hepatocellular carcinoma; HFD: High-fat diet; HSC: Liver astrocytes; NAFLD: Non-alcoholic fatty liver disease.
G protein-coupled receptor GPR49 GPR49, a G protein-coupled receptor with unidentified ligands, is highly expressed in human hepatocellular carcinoma (HCC) cell lines PLC/ PRF/5 and HepG2. In addition, overexpression of GPR49 was shown in HCC tissue with mutation of beta-catenin exon three. Another single G protein-coupled receptor, GPR137, is also widely expressed in human liver cancer cell lines, such as HepG2 and Bel7404. Depletion of GPR137 by lentiviral-mediated RNA interference in these two cell lines significantly inhibited proliferation and colony formation. Knockdown of GPR137 in HepG2 cells resulted in cell cycle arrest and apoptosis, suggesting that targeting GPR137 could inhibit cancer growth. Furthermore, low expression of GPR137 suggests progression of human HCC and low survival.
GPR132 or G2A receptor The GPR132 or G2A receptor is a proton-sensing G protein-coupled receptor and plays an important role in cell cycle and proliferation, oncogenesis, and immune response. GPR132 is also involved in hepatic lipid metabolism and gallstone formation in mice, as GPR132-deficient mice fed a high-fiber diet rapidly develop gallstones and have a high cholesterol saturation index.

2. Not all G protein-coupled receptors protect against liver disease

Succinate is increased in fatty liver cells of a high-fat/calorie-plus-fructose and high-glucose diet in water-drinking rats. Succinate exposure upregulated the expression of GPR91 in primary and immortalized HSCs, increasing the expression of ECM proteins by these cells. Inhibition of GPR91 expression by shRNA-containing virus reduces succinate-mediated HSC activation. Meanwhile, expression of GPR91 was correlated with fibrosis severity in human NASH biopsies. GPR55 and its endogenous ligand, l-α-lysophosphatidylinositol are positively correlated with obesity and type 2 diabetes (T2D). Furthermore, GPR55-deficient (GPR55 -/-) mice showed impaired insulin signaling as evidenced by decreased phosphorylation of protein kinase B and its downstream targets, with a significant increase in total body fat and liver fatty acid synthesis, which can lead to the development of hepatic steatosis.
In the same study, the author also found that lysophosphatidylinositol activated mouse H4IIE hepatocytes and human HepG2 hepatocytes through GPR55 to enhance insulin-dependent protein kinase B phosphorylation. Removal of GPBAR1, a G protein-coupled receptor for secondary BAs, increases the severity of acetaminophen-induced liver injury. Furthermore, GPBAR1 agonism mediates the axial expression of the chemokine CCL2 and its receptor CCR2 in the interface of hepatic sinusoidal cells.
3. G protein-coupled receptor signaling and regulatory proteins In general, G protein-coupled receptors are associated with distinct G protein families, including Gs, Gi, and Gq. For example, the glucagon receptor most expressed in hepatocytes is associated with the excitatory G proteins, Gs. Heterotrimeric G proteins are involved in the signaling of approximately 800 G protein-coupled receptor family members. Several of these signaling pathways play an important role in liver metabolism. For example, ablation of the Gα 12 protein (Gα 12) significantly increased starvation-induced fat accumulation in the liver of mice, and Gα 12 expression was also decreased in liver biopsies of NAFLD patients.
A mechanistic study showed that, Gα 12 regulates mitochondrial respiration through regulation of sirtuin 1 and peroxisome-activated receptor alpha expression. Furthermore, the expression of Gα12 was associated with the overall survival of HCC patients. Understanding the role of G protein in the liver also opens up the role of G protein-coupled receptors in liver metabolism and disease progression.

4. Regulators of G protein G signaling (RGS) that negatively regulate receptor signaling in association with the G protein RGS5 may protect against NAFLD and NASH. In the liver, RGS5 is an essential molecule that protects against the progression of NAFLD. RGS5 binds directly to beta-activated growth factor kinase 1 (TAK1) and inhibits its phosphorylation and subsequent pathways of c-Jun N-terminal kinase/p38. RGS5 is a promising target molecule for fine-tuning beta-activating transforming growth factor kinase 1 activity and processing NAFLD. Activated HSCs are one of the major sources of fibroblasts in many types of liver injury, producing ECM proteins. G protein-coupled receptor-mediated signaling plays an important role in HSC contraction, migration, and activation. In addition, the signaling of most G protein-coupled receptors via G protein is regulated by G protein-coupled receptor kinases (GRKs) that are also active in the pathogenesis of liver injury. For example, GRK2 (GRK2 +/-) heterozygous mice showed reduced triglyceride levels and a reduced liver-to-body ratio compared with wild-type mice when fed a diet deficient in methionine and choline. Increased levels of GRK2 protein and mRNA were also detected in liver biopsies of steatosis and NASH patients. Furthermore, high GRK2 expression magnifies palmitic acid-activated lipid accumulation in human hepatocytes.

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References:
Yang M, Zhang CY. G protein-coupled receptors are potential targets for the treatment of nonalcoholic fatty liver disease. World J Gastroenterol 2021; 27 (8): 677-691 [PMID: 33716447 DOI: 10.3748 / wjg.v27.i8.677 ]