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Gokul C Das, Ph. D Department of Medicine Baylor College of Medicine, Houston, TX

Dysregulation and Interaction of metabolic pathways in HCV induced insulin resistance and implication in therapeutic development. Gokul C Das, Ph. D Department of Medicine Baylor College of Medicine, Houston, TX 4th World Virology Congress San Antonio October 6-8, 2014.

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Gokul C Das, Ph. D Department of Medicine Baylor College of Medicine, Houston, TX

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  1. Dysregulation and Interaction of metabolic pathways in HCV induced insulin resistance and implication in therapeutic development Gokul C Das, Ph. D Department of Medicine Baylor College of Medicine, Houston, TX 4th World Virology Congress San Antonio October 6-8, 2014

  2. HCV is considered as a metabolic disease • Over 170 million people world wide is infected with HCV, are at high risk for hepC, liver cirrhosis, liver cancer or type II diabetes. • Induces insulin resistance (IR); IR accelerates the progression of liver disease and makes treatment difficult • Needs a successful vaccine and/or an well- tolerated and cost-effective treatment strategy.

  3. Recent Development in Therapy Cure for HCV by multiple oral therapySide effects and not cost-effective$1000 /tablet (sofosbuvir, polymerase inhibitor)$84,000 (3m Course)$195,000 (per cure)Majority of HCV infection is in developing countries. Need a cost-effective and well-tolerated therapy or vaccination program

  4. Questions? • How does chronic HCV infection induce insulin resistance (IR)? • How does IR affect the outcome of IFN-based therapeutic response? • How to develop a well-tolerated and cost effective treatment strategy?

  5. Hypothesis:IRS-1 phosphorylation at Ser 312 is a mediator for insulin resistance (IR) in HCV infection that involves dysregulation and interaction among metabolic pathways down stream.

  6. OUR GOALS AND STRATEGY CHRONIC INFECTION IN LIVER CELL LINE (Huh. HCV2a) DEVELOPMENT OF INSULIN RESISTANCE AND MOLECULAR BASIS OF IR AND IFN RESPONSE DISTURBANCE IN GLUCOSE HOMEOSTASIS DISRUPTION IN INSULIN SIGNALING IDENTIFY mi RNA TARGETS AND PATHWAYS INVOLVED HUMANIZED MICE MODEL THERAPEUTIC DEVELOPMENT

  7. Insulin Insulin Glut IRc IRc Plasma Membrane Insulin signaling pathway Glucose uptake IRS-1/2 GSK-3 Glycogen Synthase(GS) Glycogen Synthesis PI-3K Akt473 mTORC1/C2 Beclin 1 Bcl-2/ Bcl-XL Glut Vesicle Apoptosis Autophagy

  8. Pathways for glucose homeostasis, insulin signaling and autophagy leading to IR in HCV infection is activated early

  9. Reduced glucose uptake in infected Cells

  10. MOI: 0 2 10 .03 .05 .06 .16 .47 1.22 Fig. 5C

  11. Huh Huh.HCV 50 100 50 100 IRS-1 .06 .03 .99 1.01 p-IRS-1 .07 .04 1.22 .90

  12. p- Akt .36 .54 1.38 1.92 p-GSK-3α .06 .03 .05 .04 p-GSK-3β 1.49 1.37 1.31 1.20

  13. MOI: 0 1 2 Atg12-Atg5 .65 .78 1.30 1.38 1.32 2.61 Beclin1 .15 .27 1.16 1.05 1.49 2.44

  14. Inhibition of autophagy reduces IRS-1Ser312 and GS Ser641 phosphorylation

  15. IRS-1 Ser312, Beclin 1 and Bcl-XL present in the same immunocomplex suggesting they interact

  16. Energy Sensors AMPK and mTORAMPK is activated during liver stress and is involved in energy regulation, autophagy and inflammationmTOR is inhibited under nutritional stress and autophagy HCV stress -----AMPK-------mTOR -----Autophagy

  17. AMPK-mTOR pathway: AMPK phosphorylation and inhibition by IFNα

  18. AMPK ---- 0.34 0.54 0.48 0.35 0.25 0.23 0.48 0.52 P-AMPK ---- 0.23 0.19 1.40 0.53 0.80 0.80 0.01 0.01 Ratio 0.60 0.40 2.90 1.60 3.20 3.50 0.02 0.02

  19. S- 0.31 .08 1.45 0.77 0.71

  20. mTORphosphorylation and inhibition by IFNα

  21. Interaction of metabolic pathways with GSK-3 at the center of interaction

  22. IFN IFN Insulin Cross talk between Insulin and IFN signaling IRc IFN R1/2 IFN R1/2 JAK1 IRS-1/2 JAK1 TYK2 TYK2 IRS-1/2 Glucose uptake STATs PI-3K GSK-3α/B Glycogen synthase PI-3K Akt Akt mTOR Autophagy ISG Protein Translation

  23. Fig.8. Strategy for inhibition of major target proteins (Akt, Gsk-3, mTOR, AMPK) and effect on the pathway

  24. Summary and Discussion • HCV infected cells show disruption in glucose homeostasis (reduced glucose uptake and inactivation of GS by Ser641) and it is activated within 2 weeks • Insulin signaling pathway ( IRS-1-PI-3K-Akt-GSK-3) is dysregulated • Autophagy is linked with IR and inhibition of autophagy inhibits IRS-1, GSK-3 beta and GS ser 641 phosphorylation • Key proteins from all three major pathways interact • Phosphorylation of GSK-3 beta, AMPK or mTOR are all inhibited by IFN-alpha suggesting as potential therapeutic targets. • Phosphorylation of GSK-3 beta, AMPK and mTOR

  25. Acknowledgement • Blaine Hollinger, MD • David Gallardo Charles Rice, MD • Wei Chen Robert Purcell, MD • Cai Guangquo Stan Lemon, MD • Liping Bai, MD T. Wakita, MD • Karina Zheng, MD George Luo, MD Xianfan Huang, Ph.D Funding: Eugene B Casey Fund Carpenter fund Gulf Coast Regional Blood Center, Houston

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