STEVEN A. WEINMAN, M.D., Ph.D.
Professor of Internal Medicine, and Neuroscience and Cell Biology
Mitochondrial function and oxidative stress in Hepatitis C; HCV- alcohol interactions; Trafficking and function of hepatic chloride channels
Phone: (409) 772.4286 | Fax: (409) 747.2187 | E-mail: sweinman@utmb.edu
Websites: http://www.utmb.edu/ncb/Faculty/WeinmanSteven.html
"Our lab focuses on the mechanisms of cellular pathogenesis of liver diseases, particularly Hepatitis C and alcoholic liver disease. We use approaches from Clinical Hepatology, Cell Biology and Virology to explore several clinically important aspects of liver injury."
RESEARCH INTERESTS
The major interest in the lab is in mitochondrial function in Hepatitis C. It has been well established that chronic hepatitis C generates a state of hepatic oxidative stress that is more pronounced than that seen in other inflammatory liver diseases. Our previous work, as well as that of others, has established that the HCV core protein interacts directly with mitochondria where it causes oxidation of the glutathione pool, inhibition of complex I activity, increased reactive oxygen species production and enhanced sensitivity to oxidant-induced cell death. Several ongoing projects in the lab are examining the mechanisms of these effects, their implications for liver disease, and the potential of developing new therapeutic targets. Specific projects are:
- Determining effects of core protein on mitochondrial calcium transport and ER-mitochondrial interactions.
- Role of redox signaling events in viral replication and innate immune signaling.
- Mechanisms of accelerated liver injury caused by HCV and alcohol and potential for use of mitochondrially-directed antioxidant therapy to improve outcomes.
A second interest in the lab is mechanism of regulation of pH in intracellular vesicles in hepatocytes. This is a process that is regulated by the coordinated action of the vacuolar proton ATPase and ClC family chloride channels. In hepatocytes these processes are critical for lysosomal function, heavy metal toxicity, and trafficking of viruses and other pathogens. Intravesicular pH control is critical to the lifecycle of Hepatitis C virus and an HCV protein, p7, has been suggested to function as a proton channel necessary for pH control and formation of active virions. We are exploring this interaction between intracellular pH and viral lifecycle. Specific projects are:
- Mechanisms of trafficking and interaction of ClC chloride channels with the endocytic apparatus
- Role of vesicular acidification in control of HCV entry
- Role of viral ion channels in HCV virion maturation
PUBLICATIONS
- Okuda, M.; Li, K.; Beard, M.R.; Showalter, L.A.; Scholle, F.; Lemon, S.M.; Weinman, S.A. Mitochondrial injury, oxidative stress and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366-375, 2002.
- Li, X.; Wang, T.; Zhao, Z.; Weinman, S.A. The ClC-3 chloride channel promotes acidification of lysosomes in CHO-K1 and Huh-7 cells. Am. J. Physiol. Cell Physiol. 182:C1483-C1491, 2002.
- Li, X.; Weinman, S.A. MRP-2 modulates the activity of chloride channels in isolated hepatocytes. Hepatology 36:65-71, 2002.
- Wang, T.; Weinman, S.A. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes formation of holoceruloplasmin. Gastroenterology. 126:1157-1168, 2004.
- Otani, K.; Korenaga, M.; Beard, M.R.; Li, K.; Singh, A., Weinman, S.A. Showalter, L.A.,Wang, T., HCV core protein, CYP2E1 and alcohol produce mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology, 128:96-107; 2005.
- Korenaga, M., Wang, T., Li, Y., Showalter, L.A., Chan, T., Sun, J., Weinman, S.A., Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem, 29:1753-1757, 2005.
- Loo, YM., Owen, DM., Li, K., Erickson, AK., Johnson, CL., Fish, CL., Carney, DS., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Satio, T., Lee, WM., Hagedorn, CH., Lau, DT., Weinman, SA., Lemon, SM., Gale, M, Jr. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA, 103:6001-6006, 2006.
- Wang, T.; Weinman, S.A. Causes and consequences of mitochondrial reactive oxygen species generation in hepatitis C. J Gastroenterol Hepatol., 21 Suppl 3:S34-7, 2006.
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