The Role of GLP1-RAs in Direct Modulation of Lipid Metabolism in Hepatic Tissue as Determined Using In Vitro Models of NAFLD

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the progression of NAFLD to severe hepatic conditions. In this review article, we discuss the role of GLP-1 and GLP-1RA in the treatment of NAFLD using human hepatocyte models.

Keywords: GLP-1; GLP-1RA; NAFLD; NASF; NASH; cell culture; in vitro; lipid metabolism; liraglutide; semaglutide.

Figure 1

GLP-1RA effects in NAFLD cell culture models. ROS: reactive oxygen species; DNL: de novo lipogenesis; FFAs: free fatty acids; FA: fatty acid; ER: endoplasmic reticulum; GLP-1RA: glucagon-like peptide 1 receptor agonists; NASH: non-alcoholic steatohepatitis; NASF: non-alcoholic steatofibrosis. Green arrow: Processes result in ameliorated steatosis; Red arrow: Processes result in inhibition of NAFLD progression to NASH/NASF/cirrhosis. Figure created with Servier Medical Art, https://smart.servier.com/.