While expression of genes involved in fatty acid synthesis was prevented by blockade of A1R, decreased expression of genes involved in fatty acid metabolism was prevented by blockade of A2BR.[63, 65] Thus, depending on the cells and cellular receptors, adenosine can induce contrasting effects cellular injury, fibrosis, and steatosis. The complexity of adenosine signaling requires further testing of specific receptor agonists and antagonists.[63] The regulation of energy

balance in peripheral tissues (including muscle, adipose, and hepatic tissue) involves buy R788 the central and enteric nervous system, and is influenced by humoral factors that control appetite and physical activity. Signaling through satiety-inducing hormones[66] and endocanabinoids[67]

is deregulated in NASH, contributing to adipose tissues expansion and hepatic inflammation. Glp-1 and gastric inhibitory polypeptide belong to the class of incretins, which are released from enterocytes in response to nutrient uptake. Especially, Glp-1 regulates postprandial insulin release, inhibits glycolytic glucagon, and suppresses appetite.[68] Locally and in the blood, rapid degradation ZVADFMK of Glp-1 is mediated by the membrane-anchored enzyme DPP-IV, which is expressed prominently on epithelia, endothelial cells, and lymphocytes. While indirect and direct Glp-1 agonists have been introduced in the treatment of diabetes, their potential

in NASH is less clear. DPP-IV activity is increased in NASH,[69] and the DDP-VI inhibitors, vildagliptin N-acetylglucosamine-1-phosphate transferase and linagliptin, improved hepatic steatosis, adipose tissue inflammation, and insulin sensitivity in obese and diabetic Zucker rats and in a high-fat diet model in mice.[70, 71] The more protease-resistant, direct-acting Glp-1 agonists, exenatide and liraglutide, showed similar, if not better, therapeutic efficacy. Liraglutide corrected impaired fatty acid beta-oxidation in a rodent model with high dietary trans fats and fructose-enriched drinking water.[72] In a high-fat model using wild-type C57Bl6 and ob/ob mice, the exenatide analogue AC3174 attenuated weight gain and mitigated elevations of ALT and hepatic triglycerides.[73] Exenatide also reduced ER stress-related hepatocyte cell death and increased protective macroautophagy in response to treatment with saturated and unsaturated fatty acids.[74] Thus, enhancement of incretin signaling showed modest to considerable improvements in vitro and in animal models of NASH. Since these drugs have shown safety in patients with type 2 diabetes, clinical studies in patents with NAFLD are warranted. PPARs belong to the class of nuclear receptors that regulate expression of genes involved in lipid and glucose homeostasis but also modulate (hepatic) inflammation and fibrosis.