title: Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice.
abstract: 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.
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lebrun
authors.forename: Olivier
authors.initials: O
authors.lastname: Molendi-Coste
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lanthier
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Peter
authors.initials: P
authors.lastname: Stärkel
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Leclercq
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D004002:Clodronic Acid / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006878:Hydroxides / Q000494:pharmacology; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D006878:Hydroxides; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D004002:Clodronic Acid; C006253:pirinixic acid; C031356:hydroxide ion; D005947:Glucose