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Richard M. Green, MDAssociate Professor
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Non-Alcoholic Fatty Liver Disease (NAFLD) is now the leading cause of abnormal liver function tests in the United States and developed countries. It is associated with the metabolic syndrome and is a growing problem due to the epidemic of obesity. Unfortunately, the molecular mechanisms and genetics of this common hepatic disorder remain poorly understood. Our laboratory focuses on delineating the molecular mechanisms of injury in murine models of NAFLD. In addition, we are utilizing Quantitative Trait Loci (QTL) Analysis in order to identify the genetic mechanisms that may be important for disease development and progression.
Molecular Mechanisms of Fatty Liver Disorders
My laboratory has developed and utilized several nutritional murine models to study the mechanisms responsible for the development of fatty liver disease. Methionine-choline deficient (MCD) and high-fat high-caloric (HFHC) diets are utilized in order to characterize the signaling pathways that are important for hepatic injury and fibrosis. The unfolded protein response (UPR), endoplasmic reticulum (ER) stress, oxidative stress and fibrogenesis pathways that are activated in these nutritional models of fatty liver disease are being investigated. In addition, genetic and pharmacologic approaches to prevent disease progression are being investigated. Several inbred strains and transgenic mice are used to identify the cellular genes that are important in this pathophysiologic process.
Hepatic Bile Salt Metabolism and Gene Regulation
For the past several years, the laboratory of the PI has performed physiologic studies in hepatobiliary lipid secretion. We have previously cloned the mouse liver canalicular bile salt transporter (Abcb11) and developed transgenic mice which over-express this gene in the liver. The phenotype of this mouse includes altered susceptibility to the development of fatty liver disorders, an increased propensity to develop gallstones, obesity, and alterations of hepatic and systemic lipid metabolism. In addition, gene regulation by bile salts in the FXR-SHP and G-protein signaling pathways are being actively investigated. Polymorphisms of ABCB11 are also being examined in translational human studies.
Quantitative Trait Loci (QTL) Analysis of Fatty Liver Genes
For the past several years, the laboratory has focused on identifying inbred strains of mice with differing susceptibility to develop fatty liver disorders. We have exploited these differences of disease susceptibility in order to perform QTL analysis to identify loci that are important for the development and progression of fatty liver disorders. Ongoing studies will utilize standard genetic techniques for QTL analysis to identify the genetic loci, fine map the loci and identify the actual genes that are responsible for NAFLD.
Nie W, Sweetser S, Rinella M, Green RM. Transcriptional Regulation of Murine Slc22a1 (Oct1) by Peroxisome-proliferator agonist receptor (PPAR)-alpha and -gamma. Am J Physiol Gastrointest Liver Physiol. Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G207-12.
Sundaram SS, Whitington PF, Green RM. Steatohepatitis develops rapidly in transgenic mice over-expressing Abcb11 fed a methionine-choline deficient diet. Am J Physiol Gastrointest Liver Physiol. 2005 Jan; 288 (2) G1321-27.
Henkel, A, Zhixin W, Cohen D, Green, RM. Mice over-expressing hepatic Abcd11 rapidly develop cholesterol gallstones. Mammalian Genome. 2005 Dec;16(12):903-8.
Igolnikov, A, Green RM. Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet. J Hepatology; 2006;44(3):586-92.
Rangnekar, AS, Lammert, F, Green, RM, Identification of nonalcoholic steatohepatitis quantitative trait loci (QTLs) using silico mapping analysis. Liver Int. 2006;26(8):1000-5.
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View Publications by Richard Green listed in the National Library of Medicine (PubMed). |
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