title: Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  High-fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose metabolism, although GLP-1 receptors (GLP-1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP-1r and the effect of exenatide, a GLP-1 analogue, on hepatic signalling.
  
  
  METHODS
  The expression of GLP-1r was evaluated in human liver biopsies and in the livers of high-fat diet-treated rats. The effect of exenatide (100 nM) was evaluated in hepatic cells of rats fed 3 months with the high-fat diet.
  
  
  RESULTS
  GLP-1r is expressed in human hepatocytes, although reduced in patients with NASH. Similarly, in rats with NASH resulted from 3 months of the high-fat diet, we found a decreased expression of GLP-1r and peroxisome proliferator-activated receptor γ (PPARγ), and reduced peroxisome proliferator-activated receptor α (PPARα) activity. Incubation of hepatocytes with exenatide increased PPARγ expression, which also exerted an insulin-sensitizing action by reducing JNK phosphorylation. Moreover, exenatide increased protein kinase A (PKA) activity, Akt and AMPK phosphorylation and determined a PKA-dependent increase of PPARα activity.
  
  
  CONCLUSIONS
  GLP-1 has a direct effect on hepatocytes, by activating genes involved in fatty acid β-oxidation and insulin sensitivity. GLP-1 analogues could be a promising treatment approach to improve hepatic insulin resistance in patients with NAFLD/NASH.
authors: Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
authors: Gianluca
authors: G
authors: Svegliati-Baroni
authors: Stefania
authors: S
authors: Saccomanno
authors: Chiara
authors: C
authors: Rychlicki
authors: Laura
authors: L
authors: Agostinelli
authors: Samuele
authors: S
authors: De Minicis
authors: Cinzia
authors: C
authors: Candelaresi
authors: Graziella
authors: G
authors: Faraci
authors: Deborah
authors: D
authors: Pacetti
authors: Marco
authors: M
authors: Vivarelli
authors: Daniele
authors: D
authors: Nicolini
authors: Paolo
authors: P
authors: Garelli
authors: Alessandro
authors: A
authors: Casini
authors: Melania
authors: M
authors: Manco
authors: Geltrude
authors: G
authors: Mingrone
authors: Andrea
authors: A
authors: Risaliti
authors: Giuseppe N
authors: GN
authors: Frega
authors: Antonio
authors: A
authors: Benedetti
authors: Amalia
authors: A
authors: Gastaldelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001706:Biopsy; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism*; D004195:Disease Models, Animal; D000077270:Exenatide; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology*
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases