Mechanisms of VLDL Overproduction in Insulin Resistance
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Mechanisms of VLDL Overproduction in Insulin Resistance
- 1. VLDL ApoB mRNA Translation Degradation ER Membrane 5' 3' ApoB mRNA VLDL Assembly Degradation Secretion MTP Proteasome Hepatic Synthesis and Secretion of VLDLHepatic Synthesis and Secretion of VLDL Lipid Poor State Lipid Rich State Lipid Poor State ApoB Gene Expression VLDL Plasma Hepatocy te CE PL TG C
- 2. Mechanisms of VLDL OverproductionMechanisms of VLDL Overproduction in Insulin Resistance (Recent Progress)in Insulin Resistance (Recent Progress) • Development of a Fructose-Fed Hamster Model of Insulin Resistance • Investigations into Mechanisms of Hepatic VLDL Overproduction • Investigations into Mechanisms of Intestinal Lipoprotein Overproduction • Assessment of the Efficacy of hypolipidemic agents and insulin sensitizers in ameliorating metabolic dyslipidemia
- 3. Insulin Resistance Model Fructose-Fed Syrian Golden Hamster • Lipoprotein metabolism closely resembles that in humans • Hamster liver secretes VLDL containing only apoB100 with a density close to that of human VLDL • Hamsters develop hyperTG, hyperCHOL, & atherosclerosis in response to a modest increase in dietary cholesterol & saturated fat • Hamster can be made Obese, Hypertriglyceridemic, Hyperinsulinemic, and Insulin Resistant by carbohydrate feeding (particularly Fructose)
- 4. Male Syrian Golden Hamsters (80-100 grams)Male Syrian Golden Hamsters (80-100 grams) 60% Fructose Diet60% Fructose Diet (2 weeks)(2 weeks) Control HamstersControl Hamsters Control DietControl Diet (2 weeks)(2 weeks) Fructose-fed HamstersFructose-fed Hamsters Plasma Analysis: Glucose, TG, Chol, InsulinPlasma Analysis: Glucose, TG, Chol, Insulin Liver Perfusions >>>>>>Primary HepatocytesLiver Perfusions >>>>>>Primary Hepatocytes Intestinal Fragments >>>>>>Primary EnterocytesIntestinal Fragments >>>>>>Primary Enterocytes Experiments on Hepatic & Intestinal LipoproteinsExperiments on Hepatic & Intestinal Lipoproteins Plasma Glucose, TG, Chol, InsulinPlasma Glucose, TG, Chol, Insulin Insulin Resistance Model Fructose-Fed Syrian Golden Hamster
- 5. Evidence for Development of Insulin Resistance:Evidence for Development of Insulin Resistance: • Increased Plasma Insulin, FFA, TriglycerideIncreased Plasma Insulin, FFA, Triglyceride • Reduced whole body insulin sensitivity (based on Euglycemic-Reduced whole body insulin sensitivity (based on Euglycemic- Hyperinsulinemic Clamp Studies)Hyperinsulinemic Clamp Studies) Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425. Evidence for Development of Hepatic VLDL Overproduction:Evidence for Development of Hepatic VLDL Overproduction: • Enhanced hepatic VLDL secretion In Vivo (Triton method)Enhanced hepatic VLDL secretion In Vivo (Triton method) • Enhanced VLDL secretion by primary hamster hepatocytesEnhanced VLDL secretion by primary hamster hepatocytes ex vivoex vivo • Increased intracellular apoB stabilityIncreased intracellular apoB stability • Enhanced MTP expression (mRNA, protein, activity)Enhanced MTP expression (mRNA, protein, activity) Insulin Resistance Model Fructose-Fed Syrian Golden Hamster Hypothesis I:Hypothesis I: Insulin Resistance Induces Hepatic VLDL Overproduction Published Data:
- 6. 0 1 2 Control Fructose-Fed FreeFattyAcids (mmol/L) p=0.0045 0 100 200 300 p=0.0110 PlasmaInsulin (mmol/L) 0.0 2.5 5.0 7.5 p=0.9452 PlasmaGlucose (mmol/L) 0 1 2 3 4 5 p=0.0309 PlasmaTriglyceride (mmol/L) p= 0.0550 0.0 2.5 5.0 7.5 PlasmaCholesterol (mmol/L) A B C D E Increased Plasma Triglyceride, FFA,Increased Plasma Triglyceride, FFA, & Insulin in Fructose-Fed Hamsters& Insulin in Fructose-Fed Hamsters
- 7. Glucose(mmol/l) 0 1 2 3 4 5 6 Control (n=10) Fructose fed (n=9) Insulin(pmol/l) 0 500 1000 1500 2000 2500 3000 Ginf(µmol.kg -1 .min -1 ) 0 10 20 30 40 50 60 SI(10 6 l 2 .kg -1 .min -1 ) 0 1 2 3 4 5 6 p < 0.01 p < 0.01 p = ns p = 0.03 A B C D In Vivo Evidence of Insulin ResistanceIn Vivo Evidence of Insulin Resistance (Euglycemic-hyperinsulinemic Clamp)(Euglycemic-hyperinsulinemic Clamp) Reduced Insulin Sensitivity in Fructose-Fed HamstersReduced Insulin Sensitivity in Fructose-Fed Hamsters
- 8. Enhanced Hepatic VLDL-apoB100 SecretionEnhanced Hepatic VLDL-apoB100 Secretion in Fructose-Fed Hamstersin Fructose-Fed Hamsters (In Vivo Triton WR 1339 Studies) Time (min) 0 20 40 60 80 100 VLDL-apoB(µg/ml) 100 150 200 250 300 350 400 VLDL-apoBsecretion (µg/min) 0 2 4 6 8 10 12 * Control Fructose fed
- 9. 0 100 200 300 400 500 Fructose-FedControl VLDLapoBSecreted (%ofcontrol) ApoB100 * Overproduction of VLDL-apoB byOverproduction of VLDL-apoB by Hepatocytes from Fructose-Fed HamstersHepatocytes from Fructose-Fed Hamsters
- 10. 0 50 100 150 200 250 Control Fructose-Fed MTPActivity (PercentofControl) P=0.042 0 5 10 15 20 Control MTPRNA P<0.02 0 50 100 200 250 MTPProteinMass (percentofcontrol) 150 Fructose-Fed P=0.011 Control Fructose-Fed totalRNA/µgpg)( Protein Mass mRNA Lipid Transfer Activity Evidence for Enhanced Hepatic Microsomal Triglyceride Transfer Protein (MTP) in Fructose-Fed Hamsters
- 11. Insulin Signaling Status in Hepatocytes:Insulin Signaling Status in Hepatocytes: • Ex vivoEx vivo Analysis of Insulin Receptor, IRS-1, PI3-kinase,Analysis of Insulin Receptor, IRS-1, PI3-kinase, PTP-1B in Control and Fructose-Fed Hamster LiversPTP-1B in Control and Fructose-Fed Hamster Livers • In VitroIn Vitro Analysis of Insulin Receptor, IRS-1, PI3-kinase,Analysis of Insulin Receptor, IRS-1, PI3-kinase, PTP-1B in Primary Hepatocytes Exposed to High InsulinPTP-1B in Primary Hepatocytes Exposed to High Insulin Link between Insulin Signaling & VLDL-apoB Secretion:Link between Insulin Signaling & VLDL-apoB Secretion: • In VitroIn Vitro Analysis of ApoB Secretion in Primary HepatocytesAnalysis of ApoB Secretion in Primary Hepatocytes Exposed to High InsulinExposed to High Insulin • Inhibition of Protein Phosphatases byInhibition of Protein Phosphatases by VanadateVanadate and its Impact onand its Impact on VLDL-apoB SecretionVLDL-apoB Secretion (J. Biol. Chem. (2002) 277, 793-803) Hypothesis II:Hypothesis II: VLDL-apoB Overproduction is Linked to Hepatic Insulin ResistanceVLDL-apoB Overproduction is Linked to Hepatic Insulin Resistance Insulin Resistance Model (Fructose-Fed Hamster) Recent Data:
- 12. Y Insulin Signaling Pathway Insulin InsulinReceptorInsulinReceptor αα ββ Y PP IRSIRS ProteinsProteinsSHC Grb2 mSoS Grb2 mSoS RaS p85p85 p110p110 PI 3-KinasePI 3-Kinase PDK1 (PDK2) AktAkt PTP-1B PTP-1B PP PP PTEN aPKCs PDE BAD Anti- apoptosis Anti- lipolysis Glucose transport Gsk3ToRp70rak Glycogen synthesis Protein synthesis RAF MEK MAPK Gene Expression/ mitogenesis 90rak Plasma membrane Protein kinase CK2 Ser/Ther-p CAP CblcrkII Caveolae Glucose & Lipid metabolism Gab 1Shp-2 VanadateVanadate