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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 Int. 2011 Oct; 31(9):1285-97.LI

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 (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.

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Authors+Show Affiliations

Svegliati-Baroni G
Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
Saccomanno S
No affiliation info available
Rychlicki C
No affiliation info available
Agostinelli L
No affiliation info available
De Minicis S
No affiliation info available
Candelaresi C
No affiliation info available
Faraci G
No affiliation info available
Pacetti D
No affiliation info available
Vivarelli M
No affiliation info available
Nicolini D
No affiliation info available
Garelli P
No affiliation info available
Casini A
No affiliation info available
Manco M
No affiliation info available
Mingrone G
No affiliation info available
Risaliti A
No affiliation info available
Frega GN
No affiliation info available
Benedetti A
No affiliation info available
Gastaldelli A
No affiliation info available

MeSH

AMP-Activated Protein KinasesAnimalsBiopsyCyclic AMP-Dependent Protein KinasesDietary FatsDisease Models, AnimalExenatideFatty AcidsFatty LiverGene Expression RegulationGlucagon-Like Peptide-1 ReceptorHep G2 CellsHepatocytesHumansHypoglycemic AgentsInsulin ResistanceJNK Mitogen-Activated Protein KinasesLiverMaleNon-alcoholic Fatty Liver DiseaseOxidation-ReductionPPAR alphaPPAR gammaPeptidesPhosphorylationProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleyReceptors, GlucagonSignal TransductionTime FactorsVenoms

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21745271

Citation

Svegliati-Baroni, Gianluca, et al. "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 : Official Journal of the International Association for the Study of the Liver, vol. 31, no. 9, 2011, pp. 1285-97.
Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. 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 Int. 2011;31(9):1285-97.
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, G. N., 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 : Official Journal of the International Association for the Study of the Liver, 31(9), 1285-97. https://doi.org/10.1111/j.1478-3231.2011.02462.x
Svegliati-Baroni G, et al. 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 Int. 2011;31(9):1285-97. PubMed PMID: 21745271.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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, Y1 - 2011/02/15/ PY - 2011/7/13/entrez PY - 2011/7/13/pubmed PY - 2012/3/13/medline SP - 1285 EP - 97 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int VL - 31 IS - 9 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 (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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/21745271/Glucagon_like_peptide_1_receptor_activation_stimulates_hepatic_lipid_oxidation_and_restores_hepatic_signalling_alteration_induced_by_a_high_fat_diet_in_nonalcoholic_steatohepatitis_ L2 - https://doi.org/10.1111/j.1478-3231.2011.02462.x DB - PRIME DP - Unbound Medicine ER -