About 2-3% of the world population is infected with hepatitis C virus (HCV). Majority of HCV infections lead to chronic hepatitis. Hepatic steatosis (fatty liver) is recognized as a common histologic feature of chronic hepatitis C and occurs at an average rate of 50%. At molecular level, we and others have observed that HCV gene expression leads to alteration of cellular lipid metabolism. These changes manifest in elevated expression of genes involved in cholesterol/fatty acid biosynthetic pathways. In the current application, we propose investigate the role of HCV-induced oxidative stress in the activation of transcription factors, which include sterol regulatory element binding proteins (SREBP), liver X receptor, (LXR), PPAR1 and PCG-12. Attempts will be made to identify individual HCV gene product(s) playing a key role in steatosis. We further propose to investigate the mechanisms by which HCV gene expression impairs the lipidation of apolipoprotein B-100 (apoB). ApoB represents the major structural component of VLDL. Our recent studies identified the possible ternary complex composed of HCV NS5a protein, apoB and microsomal triglyceride transfer protein (MTP). Whether these protein-protein interactions lead to intervention of apoB lipidation will be investigated. Other possible mechanisms leading to the block in the secretion of apoB will be investigated. The results of these studies will provide unique insight into the ability of HCV gene expression in affecting lipid homeostasis and likely guide the design of future antiviral strategies in the treatment of liver disease associated with HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077704-02
Application #
7551986
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2008-01-15
Project End
2012-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
2
Fiscal Year
2009
Total Cost
$328,313
Indirect Cost
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
Kim, Seong-Jun; Ahn, Dae-Gyun; Syed, Gulam H et al. (2018) The essential role of mitochondrial dynamics in antiviral immunity. Mitochondrion 41:21-27
Kim, Seong-Jun; Jang, Jae Young; Kim, Eun-Jung et al. (2017) Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation. Hepatology 66:758-771
Syed, Gulam H; Khan, Mohsin; Yang, Song et al. (2017) Hepatitis C Virus Lipoviroparticles Assemble in the Endoplasmic Reticulum (ER) and Bud off from the ER to the Golgi Compartment in COPII Vesicles. J Virol 91:
Khan, Mohsin; Syed, Gulam Hussain; Kim, Seong-Jun et al. (2015) Mitochondrial dynamics and viral infections: A close nexus. Biochim Biophys Acta 1853:2822-33
Till, Andreas; Saito, Rintaro; Merkurjev, Daria et al. (2015) Evolutionary trends and functional anatomy of the human expanded autophagy network. Autophagy 11:1652-67
Slagle, Betty L; Andrisani, Ourania M; Bouchard, Michael J et al. (2015) Technical standards for hepatitis B virus X protein (HBx) research. Hepatology 61:1416-24
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
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; Siddiqui, Aleem (2013) Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog 9:e1003285
Bishé, Bryan; Syed, Gulam H; Field, Seth J et al. (2012) Role of phosphatidylinositol 4-phosphate (PI4P) and its binding protein GOLPH3 in hepatitis C virus secretion. J Biol Chem 287:27637-47

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