Molecular Mechanisms of Insulin Resistance in Chronic Liver Disease

Index 1. Introduction 6 1.1. Hepatitis C Virus Infection 6 Epidemiology and natural history of hepatitis C 6 The Hepatitis C Virus 6 Insulin Resistance in chronic hepatitis C 7 1.2. Non alcoholic fatty liver disease (NAFLD) 8 1.3. Overexpression of PP2Ac in chronic hepatitis C 8 Interferon (IFN) signaling is inhibited in chronic hepatitis C 8 Protein Phosphatase 2A (PP2A) 8 Upregulation of PP2A inhibits IFN signaling and increases viral replication 9 Viral induced ER stress response leads to the upregulation of PP2A 9 1.4. Regulation of glucose homeostasis in the liver 10 Insulin signaling 11 AMP activated kinase (AMPK) 12 Liver X receptor (LXR) 13 1.5. Insulin resistance in the pathophysiology of chronic liver disease 14 Insulin resistance development by hepatitis C virus 14 Insulin resistance as a key factor in pathogenesis of NAFLD 15 2. Aims 16 2.1. Insulin Resistance in the pathophysiology of chronic hepatitis C 16 2.2. Insulin Resistance in the pathophysiology of NAFLD 16 3. Material and Methods 17 Reagents, Antibodies and Cells 17 Quantitative RT-PCR 17 Fasting glucose, insulin and HOMA in mice 18 Glucose and insulin tolerance tests in mice 18 The Basel NAFLD cohort study 18 Statistical analysis 19 4. Results 20 4.1. Virus induced over-expression of protein phosphatase 2A inhibits insulin signaling in chronic hepatitis C 20 4.2. Overexpression of PP2A dysregulates glucose induced gene regulation – a role in Liver X receptor (LXR) regulation? 33 LXR in PP2Ac expressing cells (Huh7 vs. HA-PP2A cells) 33 LXR in vivo 35 4.3. Increase in gluconeogenesis as the key mechanism of HCV induced insulin resistance by PP2A ? 36 PP2Ac overexpression increases gluconeogenic gene expression in cell culture 36 B6HCV mice have an insulin resistant phenotype 37 5 Gluconeogenic gene expression in B6HCV mice 39 Gluconeogenic gene expression in patients with chronic hepatitis C 40 4.4. Insulin Resistance and natural history of NAFLD and NASH – first data from the NAFLD Cohort study in Basel 41 Patient characteristics of the Basel NAFLD cohort study population 41 Patients with NASH have significantly higher BMI and insulin resistance 41 Cytokeratin-18 fragmentation is a parameter to distinguish NAFLD from NASH 44 5. Discussion 45 5.1. Dysregulation of hepatic glucose metabolism by protein phosphatase 2A-a new mechanism for viral induced insulin resistance development 45 5.2. Systemic insulin resistance and ER stress as a drug target 47 5.3. Insulin resistance and apoptosis in the progression of NAFLD …