Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.
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Research Article|
July 25 2013
Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice
Valérie Lebrun;
Valérie Lebrun
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
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Olivier Molendi-Coste;
Olivier Molendi-Coste
1
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
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Nicolas Lanthier;
Nicolas Lanthier
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
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Christine Sempoux;
Christine Sempoux
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
†Pathology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, 1200 Brussels, Belgium
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Patrice D. Cani;
Patrice D. Cani
‡Louvain Drug Research Institute, Metabolism and Nutrition research group, Université catholique de Louvain, 1200 Brussels, Belgium
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Nico van Rooijen;
Nico van Rooijen
§Department of Molecular Cell Biology, Vrije Universiteit Medical Center, 1081 Amsterdam, The Netherlands
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Peter Stärkel;
Peter Stärkel
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
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Yves Horsmans;
Yves Horsmans
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
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Isabelle A. Leclercq
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 1200 Brussels, Belgium
Correspondence: Professor Isabelle A. Leclercq (email [email protected]).
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Publisher: Portland Press Ltd
Received:
February 08 2013
Revision Received:
June 07 2013
Accepted:
June 12 2013
Accepted Manuscript online:
June 12 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 125 (11): 501–511.
Article history
Received:
February 08 2013
Revision Received:
June 07 2013
Accepted:
June 12 2013
Accepted Manuscript online:
June 12 2013
Citation
Valérie Lebrun, Olivier Molendi-Coste, Nicolas Lanthier, Christine Sempoux, Patrice D. Cani, Nico van Rooijen, Peter Stärkel, Yves Horsmans, Isabelle A. Leclercq; Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice. Clin Sci (Lond) 1 December 2013; 125 (11): 501–511. doi: https://doi.org/10.1042/CS20130064
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