Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis

Gianluca Svegliati-Baroni, Stefania Saccomanno, Chiara Rychlicki, Laura Agostinelli, Samuele de Minicis, Cinzia Candelaresi, Graziella Faraci, Deborah Pacetti, Marco Vivarelli, Daniele Nicolini, Paolo Garelli, Alessandro Casini, Melania Manco, Geltrude Mingrone, Andrea Risaliti, Giuseppe N. Frega, Antonio Benedetti, Amalia Gastaldelli

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

Background/Aims: 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 (100nM) 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.

Original languageEnglish
Pages (from-to)1285-1297
Number of pages13
JournalLiver International
Volume31
Issue number9
DOIs
Publication statusPublished - Oct 2011

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High Fat Diet
Peroxisome Proliferator-Activated Receptors
Glucagon-Like Peptide 1
Lipids
Liver
Hepatocytes
Insulin Resistance
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
AMP-Activated Protein Kinases
Dietary Fats
Glucagon-Like Peptide-1 Receptor
Non-alcoholic Fatty Liver Disease
Fatty Acids
Exercise
Insulin
Biopsy
Glucose
exenatide
Genes

Keywords

  • GLP-1 receptor
  • Hepatic lipid oxidation
  • High-fat diet
  • NASH

ASJC Scopus subject areas

  • Hepatology

Cite this

Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. / Svegliati-Baroni, Gianluca; Saccomanno, Stefania; Rychlicki, Chiara; Agostinelli, Laura; de Minicis, Samuele; Candelaresi, Cinzia; Faraci, Graziella; Pacetti, Deborah; Vivarelli, Marco; Nicolini, Daniele; Garelli, Paolo; Casini, Alessandro; Manco, Melania; Mingrone, Geltrude; Risaliti, Andrea; Frega, Giuseppe N.; Benedetti, Antonio; Gastaldelli, Amalia.

In: Liver International, Vol. 31, No. 9, 10.2011, p. 1285-1297.

Research output: Contribution to journalArticle

Svegliati-Baroni, G, Saccomanno, S, Rychlicki, C, Agostinelli, L, de Minicis, S, Candelaresi, C, Faraci, G, Pacetti, D, Vivarelli, M, Nicolini, D, Garelli, P, Casini, A, Manco, M, Mingrone, G, Risaliti, A, Frega, GN, Benedetti, A & Gastaldelli, A 2011, 'Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis', Liver International, vol. 31, no. 9, pp. 1285-1297. https://doi.org/10.1111/j.1478-3231.2011.02462.x
Svegliati-Baroni, Gianluca ; Saccomanno, Stefania ; Rychlicki, Chiara ; Agostinelli, Laura ; de Minicis, Samuele ; Candelaresi, Cinzia ; Faraci, Graziella ; Pacetti, Deborah ; Vivarelli, Marco ; Nicolini, Daniele ; Garelli, Paolo ; Casini, Alessandro ; Manco, Melania ; Mingrone, Geltrude ; Risaliti, Andrea ; Frega, Giuseppe N. ; Benedetti, Antonio ; Gastaldelli, Amalia. / Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. In: Liver International. 2011 ; Vol. 31, No. 9. pp. 1285-1297.
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abstract = "Background/Aims: 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 (100nM) 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.",
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T1 - Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis

AU - Svegliati-Baroni, Gianluca

AU - Saccomanno, Stefania

AU - Rychlicki, Chiara

AU - Agostinelli, Laura

AU - de Minicis, Samuele

AU - Candelaresi, Cinzia

AU - Faraci, Graziella

AU - Pacetti, Deborah

AU - Vivarelli, Marco

AU - Nicolini, Daniele

AU - Garelli, Paolo

AU - Casini, Alessandro

AU - Manco, Melania

AU - Mingrone, Geltrude

AU - Risaliti, Andrea

AU - Frega, Giuseppe N.

AU - Benedetti, Antonio

AU - Gastaldelli, Amalia

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N2 - Background/Aims: 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 (100nM) 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.

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