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Slides2528

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SHAPE Society

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Slides2528

  1. 1. Postulated Mechanisms of Insulin ResistancePostulated Mechanisms of Insulin Resistance PTP-1BPTP-1B Mass & ActivityMass & Activity Impaired Phosphorylation ofImpaired Phosphorylation of Insulin Receptor, IRS-1Insulin Receptor, IRS-1 PI-3 Kinase ActivityPI-3 Kinase Activity Attenuated Insulin SignalingAttenuated Insulin Signaling Reduced Phosphorylation of ApoB orReduced Phosphorylation of ApoB or an apoB-chaperonean apoB-chaperone Enhanced Stability and Accelerated Assembly of ApoBEnhanced Stability and Accelerated Assembly of ApoB Overproduction of VLDLOverproduction of VLDL ER-60MTP
  2. 2. Intestine Contribution of the Intestinal LipoproteinsContribution of the Intestinal Lipoproteins to Metabolic Dyslipidemia in Insulin Resistanceto Metabolic Dyslipidemia in Insulin Resistance Liver ApoB48 ApoB100 Intestinal Lipoprotein Metabolism
  3. 3. DietaryDietary CholesterolCholesterol DietaryDietary FatFat LuminalLuminal TriglycerideTriglyceride LipasesLipases Bile AcidsBile Acids Fatty AcidsFatty Acids Mocellar CholesterolMocellar Cholesterol Fatty AcidsFatty Acids CholrdyrtolCholrdyrtol ApoB48 + TG + CEApoB48 + TG + CE TGTG CMCM ABCA1ABCA1 ABCG5ABCG5 ABCG8ABCG8 Fatty Acid TransportersFatty Acid Transporters Intestinal Epithelial CellIntestinal Epithelial Cell (Intake)(Intake) (Uptake)(Uptake) (Chylomicron(Chylomicron Assembly)Assembly) (Cholesterol(Cholesterol Excretion)Excretion) Intestinal Lipid Absorption (Trigleride(Trigleride Synthesis)Synthesis)
  4. 4. Hypothesis III: Fasting and postprandial hyperlipidemia in insulin resistant states may be attributable in part to intestinal oversecretion of apoB-48 containing lipoproteins Experimental Approach: • Dietary induction of an insulin resistant state in the hamster by high fructose feeding • Isolation of adult viable villi from Syrian hamster small intestine. • -In Vivo Studies to assess production rate of intestinal (apoB48- containing) lipoproteins • -Ex Vivo Studies to assess intestinal apoB48 lipoprotein synthesis and secretion, mechanisms of chylomicron assembly, role of de novo lipogenesis in intestinal lipoprotein secretion in the fasting and postprandial states

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