title: Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
abstract: OBJECTIVE
  Animal models have evidenced the role of intestinal triglyceride-rich lipoprotein overproduction in dyslipidemia. However, few studies have confronted this issue in humans and disclosed the intrinsic mechanisms. This work aimed to establish whether intestinal insulin resistance modifies lipid and lipoprotein homeostasis in the intestine of obese subjects.
  
  
  RESULTS
  Duodenal specimens obtained from 20 obese subjects undergoing bariatric surgery were paired for age, sex, and body mass index with or without insulin resistance, as defined by the homeostasis model assessment of insulin resistance. Insulin signaling, biomarkers of inflammation and oxidative stress, and lipoprotein assembly were assessed. The intestine of insulin-resistant subjects showed defects in insulin signaling as demonstrated by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, likely as the result of high oxidative stress (evidenced by malondialdehyde and conjugated dienes) and inflammation (highlighted by nuclear factor-κB, tumor necrosis factor-α, interleukin-6, intercellular adhesion molecule-1, and cyclooxygenase-2). Enhanced de novo lipogenesis rate and apolipoprotein B-48 biogenesis along with exaggerated triglyceride-rich lipoprotein production were observed, concomitantly with the high expression levels of liver and intestinal fatty acid-binding proteins and microsomal transfer protein. The presence of an aberrant intracellular cholesterol transport/metabolism was also suggested by the reduced expression of ATP-binding cassette A1 transporter and proprotein convertase subtilisin/kexin type 9.
  
  
  CONCLUSIONS
  According to the present data, the small intestine may be classified as an insulin-sensitive tissue. Dysregulation of intestinal insulin signaling, possibly triggered by oxidative stress and inflammation, was associated with exaggerated lipogenesis and lipoprotein synthesis, which may represent a key mechanism for atherogenic dyslipidemia in patients with metabolic syndrome.
authors.affiliation: From the Department of Nutrition, Université de Montréal, Research Center, CHU Sainte-Justine, Montréal, Québec, Canada (A.V., É.G., E.L.); Department of Surgery, Université Laval, Québec, Canada (P.M.); Department of Medicine, Université de Sherbrooke, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada (A.C.C.); Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada (D.R.); and Laboratoire de Lipidologie, Métabolisme et Nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada (E.L.).
authors.forename: Alain
authors.initials: A
authors.lastname: Veilleux
authors.forename: Emilie
authors.initials: E
authors.lastname: Grenier
authors.forename: Picard
authors.initials: P
authors.lastname: Marceau
authors.forename: André C
authors.initials: AC
authors.lastname: Carpentier
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004386:Duodenum / Q000201:enzymology / Q000503:physiopathology*; D050171:Dyslipidemias / Q000209:etiology / Q000503:physiopathology; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D018384:Oxidative Stress; D010766:Phosphorylation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000096:biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D015415:Biomarkers; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; C106092:microsomal triglyceride transfer protein; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: diabetes mellitus, type 2; dyslipidemias; inflammation; intestines; oxidative stress