Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, raises worldwide representing right now the prevalent liver disease in western countries

Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, raises worldwide representing right now the prevalent liver disease in western countries. Recent studies suggest that glucagon receptor signaling is definitely 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 intro to the currently available GLP-1RAs and (3) outlines the potential of growing GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD. lipogenesis, i.e., hepatic FFA synthesis, seems to contribute to lipid deposition (20). Continuous build up of lipids in hepatocytes is definitely associated with lipotoxicity, which may initiate swelling, apoptosis and ultimately fibrosis (21). The main route of hepatic excess fat oxidation is the mitochondrial tricarboxylic acid (TCA) cycle. An overactive TCA cycle tensions the endoplasmic reticulum, therefore inducing mitochondrial dysfunction and formation of reactive oxidative varieties and harmful lipid intermediates, like ceramides and diacylglycerol (22, 23). Insulin resistant adipose cells may also enhance swelling by lowering launch of anti-inflammatory adipokines such as adiponectin and increasing launch of leptin and pro-inflammatory cytokines like interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-) (24). This inflammatory milieu may contribute to hepatic insulin resistance and thus establish a vicious circle. At a molecular level, serine phosphorylation of insulin receptor substrate-1 (IRS-1) by inflammatory signals appears to be one of the key elements that disrupt insulin-receptor signaling (25). Open in a separate window Number 2 The pathophysiology of NAFLD contains fat molecules contribution, adipose and hepatic tissues insulin level of resistance, proinflammatory cytokines, lipotoxicity and oxidative tension. A lower life expectancy hepatic glucagon level of resistance (dashed lines), with Regorafenib Hydrochloride an impaired incretin impact jointly, may be extra systems. The gut-derived incretin human hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are in charge of the so-called incretin impact (i.e., the potentiation of glucose-stimulated insulin secretion after food ingestion) (26). Additionally, GLP-1 suppresses glucagon discharge from pancreatic alpha cells, delays gastric emptying and enhances satiety (27). While GIP shows very similar insulinotropic properties, it’s been proven to become a bifunctional blood sugar stabilizer by stimulating glucagon discharge in the current presence of low plasma glucose levels. Moreover, GIP receptor activation offers reported contrasting effects on satiety, caloric intake and body weight (28). It has been suggested that individuals with NAFLD have lower concentrations of biologically active incretin hormones compared to healthy individuals, which may be a consequence of an increased degradation by dipeptidyl peptidase 4 (DPP-4) (the enzyme, which under normal conditions inactivates the incretin hormones) (29) or a decreased production (30, 31). Conversely, a series of studies by our group suggest that individuals with NAFLD have normal GLP-1 and GIP plasma levels, even though they exhibit a reduced incretin effect (32). Whether a reduced incretin effect (reduced beta cell level of sensitivity to GIP and/or GLP-1) may play a role in the pathophysiology of NAFLD warrants further investigations. Glucagon is definitely a key hormone in the rules of overall energy homeostasis during the fasting state and additional energy-demanding situations. Beyond the activation of hepatic glucose production, it also affects hepatic excess fat metabolism advertising lipid oxidation Regorafenib Hydrochloride and decreasing lipid synthesis. Glucagon decreases food intake and hunger by central mechanism and by VEGFA reducing gastric emptying (33, 34). Furthermore, glucagon may display thermogenic properties, inducing an increase in energy costs through brownish adipose cells activation (13, 35). It has been hypothesized that hepatic glucagon resistance might play an important role in excess fat build up in the liver and (36). Preclinical studies in NAFLD have demonstrated Regorafenib Hydrochloride that a reduction in G protein-coupled glucagon receptor (GCGR) signaling results in an boost.