Role of hyperhomocysteinemia in liver injury and abnormal lipid metabolism (protective effect of folic acid supplementation)

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dc.contributor.supervisor O, Karmin (Physiology, Animal Science) en
dc.contributor.author Woo, Wai Hong Connie
dc.date.accessioned 2007-07-19T17:59:14Z
dc.date.available 2007-07-19T17:59:14Z
dc.date.issued 2007-07-19T17:59:14Z
dc.identifier.citation Woo CW, Siow YL, O K: Homocysteine Activates cAMP-response Element Binding Protein in HepG2 through cAMP/PKA Signaling Pathway. Arterioscler Thromb Vasc Biol. 26: 1043-1050, 2006. en
dc.identifier.citation Woo CW, Prathapasinghe GA, Siow YL, O K: Hyperhomocysteinemia Induces liver Injury in rat: Protective effect of folic acid supplementation. Biochim Biophys Acta. 1762: 656-665, 2006. en
dc.identifier.citation Woo CW, Siow YL, Pierce GN, Choy PC, Minuk GY, Mymin D, O K: Hyperhomocysteinemia Induces Hepatic Cholesterol Biosynthesis and Lipid Accumulation via Activation of Transcription Factors. Am J Physiol Endocrinol Metab. 288: E1002-E1010, 2005. en
dc.identifier.uri http://hdl.handle.net/1993/2758
dc.description.abstract Hyperhomocysteinemia, a condition of elevated blood homocysteine level, is an independent risk factor for cardiovascular diseases. Folic acid can effectively reduce blood homocysteine levels. Recent studies have shown that hyperhomocysteinemia is also associated with liver disorders. However, the underlying mechanisms remain unclear. The general objective of my study was to investigate the biochemical and molecular mechanisms of homocysteine-induced liver injury and abnormal lipid metabolism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 weeks. An elevation of serum aminotransferases activities (indicator for liver injury) and an increase in hepatic lipid peroxidation were observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production led to oxidative stress in the liver. Reduction of oxidative stress by inhibiting superoxide anion production ameliorated hyperhomocysteinemia-induced liver injury. A significant elevation of hepatic and serum cholesterol concentrations in hyperhomocysteinemic rats was observed, exclusively due to increased expression of HMG-CoA reductase in hepatocytes. The molecular mechanisms of homocysteine-induced adverse effects were further investigated in isolated rat hepatocytes and in human hepatoma cells (HepG2). Hcy stimulated HMG-CoA reductase expression in hepatocytes via activation of transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element binding protein (CREB) and nuclear factor Y (NF-Y). Activation of these 3 transcription factors was detected in hyperhomocysteinemic rat liver and in homocysteine-treated hepatocytes. Pretreatment of hepatocytes with inhibitors for individual transcription factors effectively attenuated Hcy-induced HMG-CoA reductase mRNA expression. Supplementation of folic acid in diet significantly reduced serum homocysteine level and effectively inhibited hyperhomocysteinemia-induced superoxide anion production, resulting in amelioration of oxidative stress-mediated liver injury in hyperhomocysteinemic rats. These results reflected a protective role of folic acid in hyperhomocysteinemia-induced liver injury. In conclusion, the present study demonstrates that (1) hyperhomocysteinemia can cause oxidative stress and liver injury; (2) homocysteine stimulates cholesterol biosynthesis in hepatocytes via transcriptional regulation of HMG-CoA reductase expression; (3) supplementation of folic acid offers a hepatoprotective effect during hyperhomocysteinemia. Oxidative stress and accumulation of cholesterol in the liver contribute to liver injury associated with hyperhomocysteinemia. The role of folic acid in maintaining good health may extend beyond the cardiovascular system to encompass hyperhomocysteinemia-associated liver disorders. en
dc.format.extent 3239594 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject hyperhomocysteinemia en
dc.subject liver en
dc.subject cholesterol en
dc.subject oxidative stress en
dc.subject folic acid en
dc.subject homocysteine en
dc.title Role of hyperhomocysteinemia in liver injury and abnormal lipid metabolism (protective effect of folic acid supplementation) en
dc.type info:eu-repo/semantics/doctoralThesis
dc.degree.discipline Physiology en
dc.contributor.examiningcommittee Pierce, Grant (Physiology) Dixon, Ian (Physiology) Hatch, Grant (Pharmacology) McMaster, Christopher (Dalhousie University) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note October 2007 en

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