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The Division of Gastrointestinal and Liver Diseases publishes
that work 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:
Laurie D. DeLeve, M.D., Ph.D.
Laurie DeLeve focuses her research on two main areas of interest funded by NIH. She has a longstanding 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 venoocculusive 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 how repair processes determine the outcome of sinusoidal obstruction syndrome and other diseases on the hepatic microcirculation.
The second area of research examines how cross-talk between the various cell types within the liver maintain the phenotype of
the sinusoidal endothelial cell. This is of importance because loss of the characteristic phenotype of the sinusoidal endothelial
cell, so-called capillarization, precedes fibrotic liver disease and also occurs in aging. Studies examine both the normal paracrine
and autocrine control of the sinusoidal endothelial cell, as well as the changes that occur in various models of liver disease.
Henry Chia-nan Lin, M.D.
Researchers have suggested numerous theories to explain IBS, which affects as many as 36 million Americans. In the August
issue of JAMA, Dr. Lin proposed that ordinary bacteria normally confined to the large intestine may expand into the small intestine,
prompting uncomfortable bloating and gas after meals, a change in bowel movements. IBS has long been a frustrating
diagnosis for both patients and their physicians. The bacterial hypothesis of IBS offers new hope for suffering patients by providing
a new framework for understanding the symptoms of this disorder and by pointing to new strategies for treatment. This
article presented a paradigm changing idea that functional bowel disorders such as IBS have an explanation based on abnormal
host-gut bacteria interaction rather than the traditional consideration of abnormal psychosocial learning and behavior. This discovery
is very encouraging for both patients and clinicians as the identification of a target will greatly accelerate advances in
therapy.
Equally puzzling is the condition of chronic muscle and joint ache known as fibromyalgia. In the April issue of Annals of
Rheumatic Diseases, research showed that 100% of fibromyalgia patients tested positive for small intestinal bacterial overgrowth
using the lactulose breath test. The myalgia and arthralgia of this condition is secondary to the immune response activated by
the expansion of normal colonic bacterial flora into the small intestine. This immune response may account for the muscle and
joint pains that are flu-like in fibromyalgia.
Shelly Lu, M.D.
Dr. Lu has five NIH-funded research programs. First is to study regulation of hepatic GSH synthesis. GSH is vital in defense
against oxidative stress and Dr. Lu’s laboratory has shown that the enzymes of the GSH synthetic pathway, glutamate-cysteine
ligase and GSH synthetase, are regulated transcriptionally and post-transcriptionally by hormones, oxidants and when the liver
undergoes rapid growth. They are trying to identify the molecular mechanisms of transcriptional regulation of these enzymes
which may lead to novel strategies to modulate hepatic GSH levels. Her second research program is to study regulation of hepatic
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.
Although the isoenzymes catalyze the same reaction, they differ in kinetics and regulatory properties so that MAT1A expression
results in much higher SAMe levels. Her laboratory is 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.
Her laboratory cloned the promoter region of both MAT genes and is studying their transcriptional regulation with the goal of
identifying the mechanisms of the switch in MAT gene expression in liver cancer. Her third research program focuses on abnormalities
in methionine metabolism in alcoholic liver injury. MAT activity falls in all forms of liver injury, including alcohol. In
addition, there are many other abnormalities in the methionine metabolic pathway that they believe can contribute to ethanolinduced
liver injury. These abnormalities can impact on hepatocytes as well as the non-parenchymal cells of the liver. Identifying
these abnormalities and possible therapeutic strategies are their major goals. Her fourth 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. Using a novel MAT1A knockout model developed by Dr. Lu and her collaborator,
Dr. José Mato, they showed that hepatic SAMe levels are chronically depleted in these mice. These animals are predisposed
to many forms of liver injury and develop spontaneous steatohepatitis and hepatocellular carcinoma. This model proves the
importance of maintaining normal SAMe levels and MAT1A expression in the liver. They intend to elucidate exactly how SAMe
modulates liver growth and injury. Her fifth research program is to utilize the MAT1A knockout mice as an animal model to
study the effect of ethanol. These animals have increased hepatic CYP2E1 expression and oxidative stress. They hypothesize that
these animals are predisposed to ethanol-induced liver injury and possibly pancreatic injury. The latter is because they recently
showed that MAT1A is also highly expressed in normal pancreas and in the knockout animals, pancreatic SAMe levels are dramatically
lower as in the liver. In two forms of experimental pancreatitis, administration of SAMe ameliorated the injury significantly.
Thus, the MAT1A knockout mouse may be an ideal animal model to study the injurious effect of ethanol on the liver
and pancreas, where suitable animal models are lacking.
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 gastroinestinal 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 nonsteroidal 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.
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