glucagon-like-peptide-2 and Non-alcoholic-Fatty-Liver-Disease

Non-alcoholic fatty liver disease (NAFLD) is a continuum of disorders that can range from simple steatosis to non-alcoholic steatohepatitis (NASH). As a complex metabolic disorder, the pathophysiology of NAFLD is incompletely understood. Recently glucagon-like peptide (GLP)-1 and -2 signalling has been implicated in the pathogenesis of NAFLD. The role of these gut hormones in the hepatic abnormalities is complicated by lack of consensus on the presence of GLP-1 and GLP-2 receptors within the liver. Nevertheless, GLP-1 and GLP-2 receptor agonists have been associated with alterations in lipid metabolism and hepatic and systemic inflammation, pathological abnormalities characteristic of NAFLD. Treatment with GLP-1 analogues has been shown to reverse features of NAFLD including insulin resistance, and alterations in hepatic de novo lipogenesis and reactive oxygen species. In this review, we provide an overview of the role of GLP-1 and GLP-2 in lipid homeostasis and metabolic disease including NAFLD and NASH.

Topics: Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Insulin Resistance; Lipid Metabolism; Lipids; Lipogenesis; Lipoproteins; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Signal Transduction

Total parenteral nutrition causes liver damage in patients with short bowel syndrome (SBS), in whom intestinal failure-associated liver disease (IFALD) is the strongest risk factor for mortality. We previously demonstrated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4-Is) for nutritional absorption and intestinal barrier function enhancement. Herein, we investigated the efficacy of DPP4-Is in preventing liver damage in SBS rat models.. Rats were allocated to one of five groups: normal saline (NS) + sham, DPP4-I + sham, NS + SBS, DPP4-I + SBS, and GLP-2 + SBS. DPP4-I or NS was administered orally once daily. Serum aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, and total bile acid levels were measured to assess liver function. Moreover, we evaluated liver damage using the SAF (steatosis activity fibrosis) score, which is also used to assess nonalcoholic steatohepatitis.. ALT levels and SAF scores were significantly lower in the DPP4-I + SBS group than in the NS + SBS group. Jejunal and ileal villus heights were significantly higher in the DPP4-I + SBS group than in the GLP-2 + SBS group.. The downregulation of ALT levels and SAF scores triggered by DPP4-I use may be correlated with DPP4-I-induced adiposis inhibition in SBS and NASH models. Therefore, DPP4-I may be used to reduce IFALD in patients with SBS.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 2; Liver Failure; Non-alcoholic Fatty Liver Disease; Rats; Short Bowel Syndrome

Short bowel syndrome (SBS) patients require long-term parenteral nutrition following massive bowel resection, which causes intestinal failure-associated liver disease (IFALD). Previous reports have shown that glucagon-like peptide-2 (GLP-2) resulted in the bowel adaptation for SBS. The aim of this study was to evaluate the effect of GLP-2 for IFALD in a parenterally fed rat model.. Using rat, a catheter was placed in the jugular vein, and 90% small bowel resection (SBR) was performed. Animals were divided into three groups: SBR and total parenteral nutrition (TPN) (SBS/TPN group), SBR and TPN plus GLP-2 at 1 µg/kg/h [SBS/TPN/GLP-2 (low) group], and SBR and TPN plus GLP-2 at 10 µg/kg/h [SBS/TPN/GLP-2 (high) group]. On day 13, the liver was harvested and analyzed by using nonalcoholic fatty liver disease (NAFLD) score.. Histologically, hepatic steatosis in the SBS/TPN group and SBS/TPN/GLP-2 (high) group was observed. Both steatosis and lobular inflammation score in the SBS/TPN/GLP-2 (low) group were significantly lower compared with those in the other two groups (p < 0.05). Active NAFLD score in the SBS/TPN/GLP-2 (low) group was significantly lower compared with that in the SBS/TPN/GLP-2 (high) group (p < 0.01).. Low-dose GLP-2 intravenous administration improves hepatic steatosis of IFALD following in an SBS parenterally fed rat model.

Topics: Animals; Disease Models, Animal; Glucagon-Like Peptide 2; Intestine, Small; Male; Non-alcoholic Fatty Liver Disease; Parenteral Nutrition, Total; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Fundamental complications of insulin resistance and type 2 diabetes include the development of nonalcoholic fatty liver disease and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very-low-density lipoprotein (VLDL) production. Recently, central glucagon-like peptide-2 receptor (GLP2R) signaling has been implicated in regulating hepatic insulin sensitivity; however, its role in hepatic lipid and lipoprotein metabolism is unknown. We investigated the role of glucagon-like peptide-2 (GLP-2) in regulating hepatic lipid and lipoprotein metabolism in Syrian golden hamsters, C57BL/6J mice, and Glp2r-/- mice consuming either a normal chow or high-fat diet (HFD). In the chow-fed hamsters, IP GLP-2 administration significantly increased fasting dyslipidemia, hepatic VLDL production, and the expression of key genes involved in hepatic de novo lipogenesis. In HFD-fed hamsters and chow-fed mice, GLP-2 administration exacerbated or induced hepatic lipid accumulation. HFD-fed Glp2r-/- mice displayed reduced glucose tolerance, VLDL secretion, and microsomal transfer protein lipid transfer activity, as well as exacerbated fatty liver. Thus, we conclude that GLP-2 plays a lipogenic role in the liver by increasing lipogenic gene expression and inducing hepatic steatosis, fasting dyslipidemia, and VLDL overproduction. In contrast, the lack of Glp2r appears to interfere with VLDL secretion, resulting in enhanced hepatic lipid accumulation. These studies have uncovered a role for GLP-2 in maintaining hepatic lipid and lipoprotein homeostasis.

Topics: Animals; Dyslipidemias; Fatty Liver; Gene Expression; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Lipogenesis; Lipoproteins; Lipoproteins, VLDL; Liver; Male; Mesocricetus; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease

Nonalcoholic steatohepatitis (NASH) is part of the spectrum of nonalcoholic fatty liver disease. However, there are few suitable animal models to study the pathogenesis of NASH or very limited advances in the prevention. Our aims were to establish a mouse model of NASH by intraperitoneally injecting lipopolysaccharide (LPS) at a dose of 1.5 mg per kg body weight per day for 6 weeks and to investigate the potential inhibitory effects of oat β-glucan (1%, 5%, or 10%) added to a specific pathogen-free diet. Intraperitoneal injection of LPS for 6 weeks increased serum LPS levels; decreased serum glucagon-like peptide-2 levels; triggered abnormal aminotransferase activity, glucose intolerance, and insulin resistance; and increased hepatic proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, interleukin-1β), triglyceride, and malonyl dialdehyde levels; but reduced hepatic superoxide dismutase activity. Histologic evaluation revealed evidence of hepatic steatosis, inflammation, and mild necrosis in LPS-treated mice. Dietary supplementation of oat β-glucan prevented most of the LPS-induced metabolic disorders, and improved hepatic steatosis and inflammation, although a dose-dependent effect was not observed. In conclusion, oat β-glucan could inhibit LPS-induced NASH in mice.

Topics: Animals; Avena; beta-Glucans; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxemia; Fatty Liver; Glucagon-Like Peptide 2; Glucose Intolerance; Inflammation; Insulin Resistance; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Liver; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Superoxide Dismutase; Transaminases; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain