Journal ArticleDOI
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,P. Garelli,Alessandro Casini,Melania Manco,Geltrude Mingrone,Andrea Risaliti,Giuseppe Natale Frega,Antonio Benedetti,Amalia Gastaldelli +17 more
TLDR
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.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.read more
Citations
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Journal ArticleDOI
Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study
Matthew J. Armstrong,Matthew J. Armstrong,Piers Gaunt,Guruprasad P. Aithal,Darren Barton,Darren Barton,Diana Hull,Diana Hull,Richard D. Parker,Richard D. Parker,Jonathan Hazlehurst,Kathy Guo,Kathy Guo,G. Abouda,M. Aldersley,Deborah D. Stocken,Stephen C. L. Gough,Jeremy W. Tomlinson,Rachel M. Brown,Stefan G. Hübscher,Stefan G. Hübscher,Philip N. Newsome,Philip N. Newsome +22 more
TL;DR: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
Journal ArticleDOI
Pharmacology, physiology, and mechanisms of incretin hormone action
TL;DR: Whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies are discussed.
Journal ArticleDOI
Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.
TL;DR: Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity or preventing activation of inflammatory pathways and oxidative stress hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established.
Journal ArticleDOI
AMPK, insulin resistance, and the metabolic syndrome.
TL;DR: The hypothesis that dysregulation of AMPK is both a pathogenic factor for metabolic syndrome-related disorders in humans and a target for their prevention and therapy is evaluated.
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The role of the gut microbiota in NAFLD
TL;DR: Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut–liver axis should improve the treatment of this common liver disease and its associated disorders.
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Jiro Hirosumi,Gurol Tuncman,Lufen Chang,Cem Z. Görgün,K. Teoman Uysal,Kazuhisa Maeda,Michael Karin,Gökhan S. Hotamisligil +7 more
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Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
Kerry L. Donnelly,Coleman Smith,Sarah Jane Schwarzenberg,Jose Jessurun,Mark D. Boldt,Elizabeth J. Parks +5 more
TL;DR: In this article, the authors quantified the biological sources of hepatic and plasma lipoprotein TAG in NAFLD patients, using stable isotopes for four days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipid TAG.
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Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study
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