{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:22:42Z","timestamp":1792498962204,"version":"4.5.0"},"reference-count":50,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:p>Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.<\/jats:p>","DOI":"10.1152\/ajpendo.00518.2004","type":"journal-article","created":{"date-parts":[[2005,1,11]],"date-time":"2005-01-11T22:13:46Z","timestamp":1105481626000},"page":"E1002-E1010","source":"Crossref","is-referenced-by-count":94,"title":["Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors"],"prefix":"10.1152","volume":"288","author":[{"given":"Connie W. H.","family":"Woo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaw L.","family":"Siow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant N.","family":"Pierce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C.","family":"Choy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald Y.","family":"Minuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mymin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karmin","family":"O","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000108264.67601.2C"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80122-1"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Beg ZH\n                      , Stonik JA, and Brewer HB Jr.\n                      Phosphorylation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and modulation of its enzyme activity by calcium-activated and phospholipid-dependent protein kinase.\n                      J Biol Chem\n                      260\n                      : 1682\u20131687, 1985.","DOI":"10.1016\/S0021-9258(18)89648-X"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.12.6340"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000035405.16217.86"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000027586.64231.1B"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199104253241701"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/11.5.1475"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Doumas BT\n                      .\n                      Standards for total serum protein assays\u2014a collaborative study.\n                      Clin Chem\n                      21\n                      : 1159\u20131166, 1975.","DOI":"10.1093\/clinchem\/21.8.1159"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(66)90209-0"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14234-1"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200363220-00001"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Hatch FT\n                      , Larrabee AR, Cathou RE, and Buchanan JM.\n                      Enzymatic synthesis of the methyl group of methionine. I. Identification of the enzymes and cofactors involved in the system isolated from\n                      Escherichia coli. J Biol Chem\n                      236\n                      : 1095\u20131101, 1961.","DOI":"10.1016\/S0021-9258(18)64248-6"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215593"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2961"},{"key":"R16","unstructured":"Hylemon PB\n                      , Pandak WM, and Vlahcevic ZR.\n                      Regulation of hepatic cholesterol homeostasis, In:\n                      The Liver Biology and Pathobiology\n                      , edited by Arias IM. Philadelphia, PA: Lippincott Williams & Wilkins, 2001."},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Jackson SM\n                      , Ericsson J, Mantovani R, and Edwards PA.\n                      Synergistic activation of transcription by nuclear factor Y and sterol regulatory element binding protein.\n                      J Lipid Res\n                      39\n                      : 767\u2013776, 1998.","DOI":"10.1016\/S0022-2275(20)32565-7"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211642200"},{"key":"R19","doi-asserted-by":"crossref","unstructured":"Jurevics H\n                      , Hostettler J, Barrett C, Morell P, and Toews AD.\n                      Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase.\n                      J Lipid Res\n                      41\n                      : 1048\u20131053, 2000.","DOI":"10.1016\/S0022-2275(20)32008-3"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.2.917"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002063200"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.47.29659"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1177\/002215549904700113"},{"key":"R24","doi-asserted-by":"crossref","unstructured":"Lowry OH\n                      , Rosebrough NJ, Farr AL, and Randell RJ.\n                      Protein measurement with the Folin phenol reagent.\n                      J Biol Chem\n                      193\n                      : 265\u2013275, 1951.","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"R25","unstructured":"McCully KS\n                      .\n                      Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.\n                      Am J Pathol\n                      56\n                      : 111\u2013128, 1969."},{"key":"R26","unstructured":"Mudd SH\n                      , Levy HL, and Skovby F.\n                      Disorder of transsulfuration. In:\n                      The Metabolic and Molecular Bases for Inherited Diseases\n                      (7th ed.), edited by Scriver CR, Beaudet AL, Sly WS, and Valle D. New York: McGraw-Hill, 1995."},{"key":"R27","doi-asserted-by":"crossref","unstructured":"Nakanish M\n                      , Goldstein JL, and Brown MS.\n                      Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase.\n                      J Biol Chem\n                      263\n                      : 8929\u20138937, 1988.","DOI":"10.1016\/S0021-9258(18)68397-8"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.46.28784"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202135200"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1995.03530190040032"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2760(98)00086-1"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300923200"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(91)90257-4"},{"key":"R34","doi-asserted-by":"crossref","unstructured":"Outinen PA\n                      , Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI, and Austin RC.\n                      Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells.\n                      Blood\n                      94\n                      : 959\u2013967, 1999.","DOI":"10.1182\/blood.V94.3.959.415k20_959_967"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(79)90262-X"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1021\/bi00664a010"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.49.1.31"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.35623"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108451200"},{"key":"R40","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2002.5491"},{"key":"R41","doi-asserted-by":"crossref","unstructured":"Sitrin RG\n                      , Pan PM, Srikanth S, and Todd RF III.\n                      Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes.\n                      J Immunol\n                      161\n                      : 1462\u20131470, 1998.","DOI":"10.4049\/jimmunol.161.3.1462"},{"key":"R42","doi-asserted-by":"crossref","unstructured":"Sung FL\n                      , Zhu TY, Au-Yeung KKW, Siow YL, and O K.\n                      Enhanced MCP-1 expression during ischemia\/reperfusion injury is mediated by oxidative stress and NF-\u03baB.\n                      Kidney Int\n                      62\n                      : 1160\u20131170, 2001.","DOI":"10.1111\/j.1523-1755.2002.kid577.x"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.13.3293"},{"key":"R44","doi-asserted-by":"crossref","unstructured":"Ueland PM\n                      , Helland S, Broch OJ, and Schanche JS.\n                      Homocysteine in tissues of the mouse and rat.\n                      J Biol Chem\n                      259\n                      : 2360\u20132364, 1984.","DOI":"10.1016\/S0021-9258(17)43360-6"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.21.12247"},{"key":"R46","unstructured":"Wang G\n                      , Woo CW, Sung FL, Siow YL, and O K.\n                      Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules.\n                      Arterioscler Thromb Vasc Biol\n                      22\n                      : 77\u201383, 2002."},{"key":"R47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.5.1585"},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199804093381507"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11596"},{"key":"R50","unstructured":"Wilce PA\n                      and Kroon PA.\n                      Assay of 3-hydroxy-3-mthylglutaryl coenzyme A (HMG-CoA) reductase. In:\n                      Lipoprotein Analysis. A Practical Approach\n                      , edited by Converse CA and Skinner ER. Oxford, UK: IRL Press, 1992."}],"container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpendo.00518.2004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T09:53:34Z","timestamp":1682934814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpendo.00518.2004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,5]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2005,5]]}},"alternative-id":["10.1152\/ajpendo.00518.2004"],"URL":"https:\/\/doi.org\/10.1152\/ajpendo.00518.2004","relation":{},"ISSN":["0193-1849","1522-1555"],"issn-type":[{"value":"0193-1849","type":"print"},{"value":"1522-1555","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,5]]}}}