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.

Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity

“…The main mechanism of action of these GLP-1RA is the stimulation of the GLP-1R that triggers the activation of several metabolic pathways involved in insulin secretion, lipid metabolism, energy expenditure, pro-survival and anti-apoptotic cellular signaling, and oxidative stress prevention, in several tissues like the pancreas, central nervous system, heart, muscle, kidneys, gut, among others ( 15 ). The wide distribution of the GLP-1R has allowed the study of semaglutide and liraglutide pharmacological protocols to improve metabolic diseases in several experimental models ( 26 , 40 , 48–50 ). The assessment of these GLP-1RA could elucidate the role of these drugs in the cellular signaling process of obese-related diseases, which could support the development of new pharmacological approaches.…”

“…The AMPK pathway also plays a role in inhibiting lipogenesis by regulating lipogenic genes like acetyl-CoA carboxylase. Inhibition of the acetyl-CoA carboxylase suppresses the de novo lipogenesis and improves fatty acids oxidation ( 37 , 40 ).…”

A Retrospective Analysis of Glucagon-Like Peptide 1 Receptor Agonists in Treating Type 2 Diabetes Mellitus Complicated by Nonalcoholic Fatty Liver Disease

“…Currently, it is widely believed that Journal of Biosciences and Medicines the role of GLP-1 in the liver is mediated by an indirect pleiotropic mechanism, which encompasses various functions. It inhibits glucagon release, increases insulin secretion, slows gastric emptying, and enhances satiety [12]. Liraglutide has gradually become the first-line treatment for diabetic patients.…”

Lipid-Lowering Therapy after Acute Coronary Syndrome

“…The role of GLP-1RAs in modulating lipid metabolism extends to the liver, with studies indicating a reduction in hepatic steatosis by inhibiting de novo lipogenesis and improving mitochondrial function in hepatocytes. These hepatoprotective effects are mediated through the downregulation of genes involved in lipogenic pathways, contributing to an improved lipid profile [83].…”