Hepatitis C virus infections most often lead to chronic hepatitis, which can progress to liver cirrhosis and hepatocellular carcinoma. The infection is also associated with steatosis. HCV alters lipid homeostasis. HCV stimulates lipogenesis, impairs mitochondrial ?-oxidation and lipid export. These altered lipid metabolic activities benefi viral infectious process. Several lipid molecules affect viral replication, assembly, maturation and secretion. In this resubmission of our application, we continue to investigate molecular mechanism(s) associated with HCV-induced alteration of host lipid metabolism. Our current focus will be on effect of HCV gene expression on mitochondrial ?-oxidation and the mitochondrial dysfunctions associated with chronic hepatitis C. We propose to investigate the effects of HCV gene expression on mitochondrial enzymes involved in lipid metabolism, and mechanisms of clearance of damaged mitochondria via mitophagy. These studies provide a unique insight and open avenues of investigations into HCV-associated liver disease pathogenesis

Public Health Relevance

Hepatitis C virus (HCV) infects about 2-3% of world population. HCV infection is a major risk for the development of hepatocellular carcinoma (HCC) and an indicator for liver transplant. This proposal aims to examine the role of HCV on mitochondrial metabolism, physiology and dynamics and its contribution to liver disease pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK077704-06A1
Application #
8655441
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2007-04-01
Project End
2017-12-31
Budget Start
2014-01-20
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$337,125
Indirect Cost
$119,625
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Syed, Gulam Hussain; Tang, Huihui; Khan, Mohsin et al. (2014) Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation. J Virol 88:2519-29
Kim, Seong-Jun; Syed, Gulam H; Khan, Mohsin et al. (2014) Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proc Natl Acad Sci U S A 111:6413-8
Kim, Seong-Jun; Syed, Gulam H; Siddiqui, Aleem (2013) Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog 9:e1003285
Syed, Gulam H; Siddiqui, Aleem (2011) Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus. Hepatology 54:1936-46
Amako, Yutaka; Syed, Gulam H; Siddiqui, Aleem (2011) Protein kinase D negatively regulates hepatitis C virus secretion through phosphorylation of oxysterol-binding protein and ceramide transfer protein. J Biol Chem 286:11265-74
Syed, Gulam H; Amako, Yutaka; Siddiqui, Aleem (2010) Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab 21:33-40
Amako, Yutaka; Sarkeshik, Ali; Hotta, Hak et al. (2009) Role of oxysterol binding protein in hepatitis C virus infection. J Virol 83:9237-46