AMPK in the small intestine in normal and pathophysiological conditions

E. Harmel , E. Grenier , A. Bendjoudi Ouadda , M. El Chebly , E. Ziv , J. F. Beaulieu , A. Sane , S. Spahis , M. Laville (1) , E. Levy

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition

The role of AMPK in regulating energy storage and depletion remains unexplored in the intestine. This study will to define its status, composition, regulation and lipid function, as well as to examine the impact of insulin resistance and type 2 diabetes on intestinal AMPK activation, insulin sensitivity, and lipid metabolism. Caco-2/15 cells and Psammomys obesus (P. obesus) animal models were experimented. We showed the predominance of AMPKalpha1 and the prevalence of alpha1/beta2/gamma1 heterotrimer in Caco-2/15 cells. The activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside and metformin resulted in increased phospho(p)-ACC. However, the down-regulation of p-AMPK by compound C and high glucose lowered p-ACC without affecting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Administration of metformin to P. obesus with insulin resistance and type 2 diabetes led to 1) an up-regulation of intestinal AMPK signaling pathway typified by ascending p-AMPKalpha(-Thr172); 2) a reduction in ACC activity; 3) an elevation of carnitine palmitoyltransferase 1; 4) a trend of increase in insulin sensitivity portrayed by augmentation of p-Akt and phospho-glycogen synthetase kinase 3beta; 5) a reduced phosphorylation of p38-MAPK and ERK1/2; and 6) a decrease in diabetic dyslipidemia following lowering of intracellular events that govern lipoprotein assembly. These data suggest that AMPK fulfills key functions in metabolic processes in the small intestine.

Mots clés: *Gene Expression Regulation; Enzymologic; AMP-Activated Protein Kinases/*metabolism; Caco-2 Cells; Carnitine O-Palmitoyltransferase/metabolism; Dimerization; Extracellular Signal-Regulated MAP Kinases/metabolism; Gerbillinae; Glycogen Synthase Kinase 3/metabolism; Insulin/metabolism; Intestine; Small/*enzymology; Lipid Metabolism; Metformin/chemistry; Microsomes/metabolism; Organ Culture Techniques; p38 Mitogen-Activated Protein Kinases/metabolism; Humans; Male; Animals; MAP Kinase Signaling System; Insulin Resistance; Phosphorylation; Lipid Peroxidation; Antioxidants/metabolism

Domaines: Sciences du Vivant [q-bio]

E. Harmel, E. Grenier, A. Bendjoudi Ouadda, M. El Chebly, E. Ziv, et al.. AMPK in the small intestine in normal and pathophysiological conditions. Endocrinology, 2014, 155 (3), pp.873-88. ⟨10.1210/en.2013-1750⟩. ⟨hal-01859006⟩