| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; National Centre for Agri-Food Research in Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
2 Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; National Centre for Agri-Food Research in Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Centre for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada
3 Centre for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada
4 Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
5 Centre for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
6 Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada; National Centre for Agri-Food Research in Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
* To whom correspondence should be addressed. E-mail: karmino{at}sbrc.ca.
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 weeks. 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.
This article has been cited by other articles:
|
|
 |
|
  S.-Y. Hwang, C. W. H. Woo, K. K. W. Au-Yeung, Y. L. Siow, T. Y. Zhu, and K. O Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-{kappa}B activation Am J Physiol Renal Physiol, January 1, 2008; 294(1): F236 - F244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Koch, B. Konig, J. Spielmann, A. Leitner, G. I. Stangl, and K. Eder Thermally Oxidized Oil Increases the Expression of Insulin-Induced Genes and Inhibits Activation of Sterol Regulatory Element-Binding Protein-2 in Rat Liver J. Nutr., September 1, 2007; 137(9): 2018 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Prathapasinghe, Y. L. Siow, and K. O Detrimental role of homocysteine in renal ischemia-reperfusion injury Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1354 - F1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. I. Stangl, K. Weisse, C. Dinger, F. Hirche, C. Brandsch, and K. Eder Homocysteine Thiolactone-Induced Hyperhomocysteinemia Does Not Alter Concentrations of Cholesterol and SREBP-2 Target Gene mRNAs in Rats Experimental Biology and Medicine, January 1, 2007; 232(1): 81 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W.H. Woo, Y. L. Siow, and K. O Homocysteine Activates cAMP-response Element Binding Protein in HepG2 Through cAMP/PKA Signaling Pathway Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1043 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Devlin and S. R. Lentz ApoA-I: A Missing Link Between Homocysteine and Lipid Metabolism? Circ. Res., March 3, 2006; 98(4): 431 - 433. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
