Cheng Ji, Ph.D.
Dr. Ji together with Dr. Kaplowitz discovered that intragastric ethanol feeding in mice induces unfolded protein response/endoplasmic reticulum (UPR/ER) stress response. The proximate cause appears to be hyperhomocysteinemia (HHcy), a well-known cause of ER stress in other contexts. HHcy appears to be due to impaired metabolism of the essential amino acid-methionine. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. HHcy, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNFa signaling. At present ER stress as an important factor in the pathogenesis of abuse of alcohol and/or drugs, metabolic disorder, mutation of genes encoding ER-resident proteins, and viral infection-induced liver disease is an exciting new hypothesis, and research is underway to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, increased S-adenosylmethionine, or stabilized major mammalian membrane phospholipids, i.e., normalized ratio of phosphatadylcholine to phosphatdylethanolamine.

Serhan Karvar, M.D.
Dr. Karvar is interested in cellular mechanisms of acid secretion in gastric parietal cells, including the roles of membrane transport proteins and proteins involved in vesicular trafficking. In gastric parietal cells, regulation of the proton pump (H,K-ATPase) is accomplished by vesicular trafficking and membrane fusion. The fusion of tubulovesicles containing H,K-ATPase with the apical plasma membrane allows the cells to pump HCl into the stomach. A number of proteins involved in vesicular transport have collectively been designated as SNARE proteins. SNAREs have been implicated in mediating membrane fusion. Using fluorescence protein constructs (GFP, YFP, CFP), we have characterized the intracellular localization and stimulation-associated distribution dynamics of SNARE proteins in live gastric parietal cells. Dr. Karvar’s results suggest that these SNARE proteins play important roles in the activation/deactivation of gastric parietal cells.

Karen L. Lindsay, M.D., M.M.M.
Dr. Lindsay is the Principal Investigator on an NIH-NIDDK sponsored project, “The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial: A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Long-term Pegylated-Interferon Alfa-2a for Treatment of Chronic Hepatitis C in Patients who Failed to Respond to Previous Interferon Therapy”. The major goal of this project is to evaluate the efficacy and safety of continuous peginterferon alpha therapy in patients with clinical compensated cirrhosis due to chronic hepatitis C who have failed to respond to previous alpha interferon therapy. Associated with this project are three funded clinical ancillary studies: the “Risk Factor Ancillary Study” which is designed to identify potentially modifiable risk factors associated with HCV disease progression, and “Cognitive Effects Ancillary Study”, in which extensive cognitive function testing is being done in order to determine the effect of chronic HCV disease and interferon treatment on cognitive function. Dr. Lindsay is also a co-PI of a collaborative “Immunology-Virology Ancillary Study” in which patient specimens are evaluated in five lab-based projects to assess the interaction between host immune and viral factors associated with disease progression and lack of virological response to treatment.

Murad Ookhtens, Ph.D.
Dr. Ookhtens (and his co-PI, Dr. Sarah Hamm-Alvarez of Pharmacy) were awarded a $415,051 shared instrumentation grant (SIG) by the National Center for Research Resources (NIH), entitled “Confocal Microscopy Imaging System.” The effort involved putting together a base of 21 investigators with 35 R01 grants. The award was used to purchase a state-of-the-art Zeiss LSM 510 confocal system, with the following capabilities: 4-fluorophore detection ±DIC or phase overlay; time-lapse and multi-time lapse; FRAP; FRET; photoactivation of GFP or KAEDE; CO2 and O2 metabolic modules for programmed live cell imaging; plus advanced LSM Software. The system was installed in the Cell and Tissue Imaging Core (HMR-610C) of the Research Center for Liver Diseases and, after all the testing and training were completed, the availability of the system to the users was announced on November 15, 2007. Any potential new users should contact Dr. Ookhtens to discuss access to the system.

Heping Yang, Ph.D., M.D.
Heping Yang together with Dr. Shelly Lu discovered that following common bile duct ligation (CBDL) or left hepatic bile duct ligation (LHBDL), the expression of p53, c-Myc and cyclin D1 increased markedly while Mnt expression decreased. Nuclear binding activity of Myc to E-box element of p53 and cyclin D1 increased, while that of Mnt decreased in a time-dependent fashion. Lithocolic acid (LCA) treatment of primary human hepatocytes and HuH-7 cells induced a similar switch from Mnt to Myc, increased p53 and cyclin D1 promoter activity, endogenous p53 and cyclin D1 expression and apoptosis. Blocking c-Myc induction in HuH-7 cells with siRNA prevented the LCA-mediated increase in p53 and cyclin D1 expression and reduced apoptosis. CBDL and LHBDL mice treated with lentivirus harboring c-myc siRNA were protected from hepatic induction of p53 and cyclin D1, switch in Mnt to Myc nuclear binding to E-box, and hepatocyte apoptosis. Thus, the switch from Mnt to Myc during BDL and in hepatocytes treated with LCA is responsible for the induction in p53 and cyclin D1 expression and contributes to apoptosis.

Thomas M. Zarchy, M.D.
Dr. Thomas Zarchy is conducting a study on the prevalence of types of IBD and response to treatment at the Roybal Clinic. They have collected a 2.5 year database on 124 patients with IBD. They are still collecting data and plan to start analyzing the data in 2008. They are interested in seeing how this low economic and educated population correlates with higher economic and educated populations with regard to diagnosis and treatment. Dr. Zarchy is submitting a paper entitled, “A Risk Profile for Advanced Neoplasms Proximal to the Sigmoid Based on Demographics and Indications.”

Faculty Research Areas

Laurie D. DeLeve, M.D., Ph.D.
Drug-Induced Hepatotoxicity
Endothelial Progenitor/Stem Cells
Hepatic Veno-Occlusive Disease
Non-Parenchymal Cell Biology

John A. Donovan, M.D.
Live Donor Liver Transplantation
Recurrent Hepatitis C After Liver Transplantation

Tse-Ling Fong, M.D.
Complications of End Stage Liver Diseases
Treatment of Chronic Viral Hepatitis

Derick Han, Ph.D.
Oxidative Stress
Redox Chemistry
Role of PKC and JNK Signaling in Liver Disease

Chaim O. Jacob, M.D., Ph.D.
Genetics of Autoimmune Disease in Mice and Humans
Molecular Mechanisms for the Role of Cytokines in Autoimmune Diseases
Role of Apoptosis in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Fariba Javadi, M.D.
Treatment of Chronic Viral Hepatitis and Malignancies of the Liver and Biliary Tract

Cheng Ji, Ph.D.
Homocysteine Metabolism
Hyperhomocysteinemia
Host-Pathogen Interactions
Pathogenesis of Alcohol and Drug-Induced Liver Injury

Neil K. Kaplowitz, M.D.
Drug Toxicity
Glutathione Metabolism
Liver Function
Pathogenesis of Alcoholic Liver Disease
ER Stress
Mitochondrial Biogenesis

Serhan Karvar, M.D.
Molecular Mechanism of Gastric Acid Secretion
Vesicle Trafficking and Membrane Fusion
Exocytosis

Michael M. Kline, M.D.
Gastroesophageal Reflux Disease and Esophageal Motor Disorders

Loren A. Laine, M.D.
GI Bleeding
Upper GI Tract Injury (NSAIDs, H. pylori)

Karen L. Lindsay, M.D., M.M.M.
Viral Hepatitis: Treatment, Serologic Testing, Mechanisms of Injury

Zhang-Xu Liu, M.D., Ph.D.
Role of Innate Immune System in Drug Hepatotoxicity

Shelly C-L. Lu, M.D.
Regulation of Hepatic GSH Synthesis
Role of Methionine Adenosyltransferase and S-adenosylmethionine in Health and Disease
Abnormal Methionine Metabolism in Alcoholic Liver Injury

Murad Ookhtens, Ph.D.
Hepatic Methylation-Remethylation-Transsulfuration Pathways
Alcoholic Liver Disease
Tracer Kinetics Using Radioactive and Stable Isotopes
Mathematical Modeling of Biological Processes/Systems

Andrew A. Stolz, M.D.
Dysregulation of Hormone Catabolism in Human Hormone-Dependent Tumors
Molecular Biology of Bile Acid Transport
NADPH Oxidoreductases

Heping Yang, Ph.D., M.D.
Comparative Molecular Biology of Methionine Cycle Enzymes
Regulation of p53 and Cyclin D1 by Toxic Bile Acid: Role of Myc-Max and Mnt-Max

Thomas M. Zarchy, M.D.
Colonic Disease
Polyps
Colon Cancer
Inflammatory Bowel Disease