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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.

Authors+Show Affiliations

Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -