Abstract
Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as fat accumulation in more than 5% of the hepatocytes
NAFLD can be subdivided according to the level of inflammation ranging from simple steatosis without inflammation to nonalcoholic steatohepatitis (NASH), which is often associated with fibrosis and over time may lead to cirrhosis and end-stage liver failure
A recent meta-analysis comprising nearly 300,000 individuals showed that patients with NAFLD have an increased risk of developing type 2 diabetes (T2D) compared to controls [hazard ratio (HR) 2.22, 95% CI 1.84–2.60], and that risk of T2D increases across the stages of NAFLD [9]
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as fat accumulation in more than 5% of the hepatocytes. It has been hypothesized that a reduction in hepatic GCGR and signaling molecules affects a feedback mechanism acting on the pancreatic alpha cells, increasing glucagon secretion, and this liver-pancreas axis might contribute to fasting hyperglucagonemia [36] In line with this hypothesis, results from our group show that individuals with NAFLD (both normoglycemic individuals and patients with T2D) exhibit significantly higher fasting plasma glucagon levels compared to matched controls without NAFLD [28]. One month-therapy with a pegylated GLP-1R/GCGR dual agonists in diet-induced obese (DIO) mice resulted in bodyweight loss and improved glycemic control These effects were coupled to an amelioration in lipid metabolism and hepatic steatosis, which markedly exceeded the effect of single GLP-1RA treatment [72]. Preliminary studies in non-diabetic obese individuals showed that simultaneous activation of GLP-1 and GIP receptors did not potentiate GLP-1-mediated effects in lowering food intake and appetite [79]
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