Keck : Department of Medicine : About the Division : Overview

The Division of Gastrointestinal and Liver Diseases represents a broad range of clinical and basic research activities from nearly all the Division’s members. Four of these stand out as seminal contributions which are highlighted as follows:

Kaplowitz receives liver society’s highest honor»
Neil Kaplowitz, director of the USC Center for Liver Diseases and the Thomas Brem/USC Associates Professor of Medicine at the Keck School of Medicine, has been named recipient of the 2006 Distinguished Achievement Award of the American Association for the Study of Liver Diseases.

Keck School Scientist Recognized
Keck School of Medicine of USC gastroenterologist Shelly Lu and Laurie DeLeve have received the Western Society for Clinical Investigation’s Outstanding Investigator Award.

Laurie D. DeLeve, M.D., Ph.D.
Laurie DeLeve focuses her research on two main areas of interest funded by NIH. She has a long-standing interest in the mechanisms of drug-induced liver injury. For several years the emphasis has been on drug-induced damage to the hepatic microcirculation, specifically hepatic sinusoidal obstruction syndrome (hepatic venoocclusive disease). These studies have uncovered the initiating mechanisms on both an ultrastructural and biochemical level. More recently this research has been extended to look at stem cell repair of the hepatic microcirculation in various forms of liver injury. This is of importance both to restore blood flow to the liver after injury, as well as to provide the cells that make the growth factor needed to regenerate the liver after injury. The second area of research examines how cross-talk between the various cell types within the liver maintain a normal healthy liver. Loss of the normal cross-talk between liver cells permits the liver to progress to chronic liver disease. A better understanding of these very early changes could ultimately provide therapeutic strategies to prevent or treat chronic liver disease.

Shelly Lu, M.D.
Dr. Lu has four active NIH-funded research programs. Her first and longest running program focuses on the regulation of hepatic GSH synthesis. GSH is vital in defense against oxidative stress and her laboratory has conclusively demonstrated that the enzymes of the GSH synthetic pathway, glutamate-cysteine ligase and GSH synthetase, are regulated transcriptionally and post-transcriptionally by hormones, oxidants and liver regeneration. Currently, she is elucidating the molecular mechanisms regarding transcriptional regulation of these enzymes; an approach which may well lead to novel strategies to enhance hepatic GSH levels. Dr. Lu’s second research program examines the hepatic regulation of methionine adenosyltransferases (MATs). MAT is a critical cellular enzyme as it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biologic methyl donor, a precursor for polyamine synthesis, and in the liver, a major precursor for GSH through the transsulfuration pathway. Two genes encode for MAT, MAT1A is expressed in normal differentiated liver and MAT2A is expressed in all extrahepatic tissues as well as in fetal liver. As the liver matures, MAT2A is replaced by MAT1A. Dr. Lu’s laboratory was the first to describe a switch from MAT1A to MAT2A expression in human hepatocellular carcinoma, which is pathogenetically important because MAT2A expression provides a growth advantage. This program is now focused on the logical next question emanating from these key observations: elucidating the molecular transcriptional mechanisms responsible for the switch in MAT gene expression in liver cancer. Dr. Lu’s third research program examines the role of SAMe in liver function and injury. Hepatic MAT activity falls in cirrhosis of all causes. This is due to both inactivation of the enzyme as well as decreased MAT1A expression. A novel MAT1A knockout model developed by Dr. Lu and her collaborator, Dr. José Mato, modeled the loss of this enzyme in the liver. Not only do these knockout animals develop spontaneous steatohepatitis, but over time they also manifest a high frequency of hepatocellular carcinoma. This model proves the importance of maintaining normal SAMe levels and MAT1A expression in the liver. Recently, they have also discovered that if hepatic SAMe is not properly metabolized as in Glycine N-methyltransferase knockout mice, liver injury and cancer also ensue. Based on these data, she is now elucidating the mechanisms by which SAMe modulates liver injury and cancer. Dr. Lu’s fourth and newest research program is to examine the role of MAT genes and SAMe in colon cancer pathogenesis and treatment. Findings from her laboratory show that MAT genes are up-regulated in colon cancer and both SAMe and its metabolite methylthioadenosine (MTA) can induce cell death selectively in colon cancer cells while sparing the normal colon epithelial cells. This may lead to a novel approach for both chemoprevention and treatment of colonic neoplasm. Thus, Dr. Lu has a well-funded laboratory dedicated to the study of methyl donors in oxidant defense mechanisms, injury, and cancers of the liver and colon

Loren A. Laine, M.D.
Low-dose aspirin is widely used for prevention of cardiovascular events. The main concern regarding the use of aspirin is the concern over gastrointestinal complications such as a bleeding ulcer. In addition, when an anti-inflammatory drug is required, it is not known whether the COX-2 specific inhibitors are safer than traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs). In the August issue of Gastroenterology, we reported the first published randomized controlled trial to assess the rate of ulcer development with low-dose aspirin and the first to assess the rate of ulcer formation with combination of low-dose aspirin and a COX-2 specific inhibitor. In this large 12-week double-blind trial in over 1,600 patients, we found that 81 mg of enteric coated aspirin did not increase the incidence of ulcers as compared to placebo, although there was an increase in erosions. Furthermore, we found that the combination of low-dose aspirin and a COX-2 specific inhibitor markedly increased ulcer incidence, to a level comparable to that of a traditional non-selective NSAID. This information is important not only to guide clinical practice, but it helps understand the pathogenetic mechanisms of GI tract injury with NSAIDs and aspirin