Document Detail


Increased lipogenesis and stearate accelerate vascular calcification in calcifying vascular cells.
MedLine Citation:
PMID:  21596756     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vascular calcification is recognized as an independent predictor of cardiovascular mortality, particularly in subjects with chronic kidney disease. However, the pathways by which dysregulation of lipid and mineral metabolism simultaneously occur in this particular population remain unclear. We have shown that activation of the farnesoid X receptor (FXR) blocks mineralization of bovine calcifying vascular cells (CVCs) and in ApoE knock-out mice with 5/6 nephrectomy. In contrast to FXR, this study showed that liver X receptor (LXR) activation by LXR agonists and adenovirus-mediated LXR overexpression by VP16-LXRα and VP16-LXRβ accelerated mineralization of CVCs. Conversely, LXR inhibition by dominant negative (DN) forms of LXRα and LXRβ reduced calcium content in CVCs. The regulation of mineralization by FXR and LXR agonists was highly correlated with changes in lipid accumulation, fatty acid synthesis, and the expression of sterol regulatory element binding protein-1 (SREBP-1). The rate of lipogenesis in CVCs through the SREBP-1c dependent pathway was reduced by FXR activation, but increased by LXR activation. SREBP-1c overexpression augmented mineralization in CVCs, whereas SREBP-1c DN inhibited alkaline phosphatase activity and mineralization induced by LXR agonists. LXR and SREBP-1c activations increased, whereas FXR activation decreased, saturated and monounsaturated fatty acids derived from lipogenesis. In addition, we found that stearate markedly promoted mineralization of CVCs as compared with other fatty acids. Furthermore, inhibition of either acetyl-CoA carboxylase or acyl-CoA synthetase reduced mineralization of CVCs, whereas inhibition of stearoyl-CoA desaturase induced mineralization. Therefore, a stearate metabolite derived from lipogenesis might be a risk factor for the development of vascular calcification.
Authors:
Tabitha C Ting; Shinobu Miyazaki-Anzai; Masashi Masuda; Moshe Levi; Linda L Demer; Yin Tintut; Makoto Miyazaki
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-19
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-04     Completed Date:  2011-09-08     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23938-49     Citation Subset:  IM    
Affiliation:
Division of Renal Diseases and Hypertension, Department of Medicine, Denver VA Medical Center and University of Colorado, Denver, Aurora, Colorado 80045, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetyl-CoA Carboxylase / genetics,  metabolism
Alkaline Phosphatase / genetics,  metabolism
Animals
Blood Vessels / metabolism*,  pathology
Calcinosis / genetics,  metabolism*,  pathology
Cattle
Cells, Cultured
Etoposide / metabolism
Lipogenesis*
Mice
Mice, Knockout
Orphan Nuclear Receptors / genetics,  metabolism
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear
Stearic Acids / metabolism*
Stearoyl-CoA Desaturase / genetics,  metabolism
Sterol Regulatory Element Binding Protein 1 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
5P30DK048520/DK/NIDDK NIH HHS; DK081346/DK/NIDDK NIH HHS; HL081202/HL/NHLBI NIH HHS; P30DK57516/DK/NIDDK NIH HHS; R01 DK081346-01A2/DK/NIDDK NIH HHS; R01 DK081346-01A2S1/DK/NIDDK NIH HHS; R01 DK081346-02/DK/NIDDK NIH HHS; R01 DK081346-03/DK/NIDDK NIH HHS; R01 DK081346-04/DK/NIDDK NIH HHS; R21 DK076009-01/DK/NIDDK NIH HHS; R21 HL109628/HL/NHLBI NIH HHS; R21 HL109628-02/HL/NHLBI NIH HHS; R25GM083333/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Orphan Nuclear Receptors; 0/Receptors, Cytoplasmic and Nuclear; 0/Stearic Acids; 0/Sterol Regulatory Element Binding Protein 1; 0/farnesoid X-activated receptor; 0/liver X receptor; 33419-42-0/Etoposide; 4ELV7Z65AP/stearic acid; EC 1.14.19.1/Stearoyl-CoA Desaturase; EC 3.1.3.1/Alkaline Phosphatase; EC 6.4.1.2/Acetyl-CoA Carboxylase
Comments/Corrections

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