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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. 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
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
Editor's Notes
Key point: The process of cholesterol absorption is complex and currently only partly understood.
Cholesterol absorption is a complex, multistep process.
Methods of affecting these processes include reducing dietary cholesterol by decreasing intake. Bile acid sequestrants such as cholestyramine and colestipol bind to bile acids, blocking their normal resorption. This increases bile acid excretion resulting in a net cholesterol loss.4,10 The packaging of cholesterol in micelles can be reduced through the use of plant stanol esters, such as sitostanol. These esters are structurally similar to cholesterol and competitively compete with cholesterol for incorporation into micelles.2,5,11,12 Since cholesterol must be packaged in micelles in order to cross the basement membrane of enterocytes, this effectively decreases cholesterol uptake and increases cholesterol secretion. ABCG5 and ABCG8 are proteins involved in sterol excretion.13 ABCA1 is up-regulated by cellular cholesterol and functions to transport cholesterol out of the cell.7-9