GPCRs get fatty: the role of G protein-coupled receptor signaling in the development and progression of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by the abnormal deposition of lipids within the liver not due to alcohol consumption, is a growing epidemic affecting over 30% of the United States population. Both simple fatty liver and its more severe counterpart, nonalcoholic steatohepatitis, represent one of the most common forms of liver disease. Recently, several G protein-coupled receptors have emerged as targets for therapeutic intervention for these disorders. These include those with known hepatic function as well as those involved in global metabolic regulation. In this review, we highlight these emerging therapeutic targets, focusing on several common themes including their activation by microbial metabolites, stimulatory effect on insulin and incretin secretion, and contribution to glucose tolerance. The overlap in ligands, localization, and downstream effects of activation indicate the interdependent nature of these receptors and highlight the importance of this signaling family in the development and prevention of NAFLD.

Keywords: GPCR; NAFLD; lipogenesis; microbiota; steatosis.

Graphical abstract

Figure 1.

G protein-coupled receptor (GPCR) signaling within the liver, small intestine, adipose tissue, and pancreas all contribute to the development of, or protection from, nonalcoholic fatty liver disease (NAFLD). By promoting insulin release and signaling, regulating lipogenesis and fibrogenesis, impacting hepatic stellate cell activation, and modulating inflammation and the inflammasome, these receptors highlight known and emerging hepatic and metabolic regulatory pathways. The numbers represent the primary sites of expression for the GPCRs (listed by GPR number) included in this review. Green arrows indicate pathways and/or proteins that are activated, whereas red arrow butts represent pathways that are downregulated upon GPCR activation. GLP-1, glucagon-like peptide 1. Figure was created with BioRender.