Increased lipogenesis and stearate accelerate vascular calcification in calcifying vascular cells.

Abstract

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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 27 Pg. 23938-49 (Jul 08 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21596756 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Liver X Receptors
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear
• Stearic Acids
• Sterol Regulatory Element Binding Protein 1
• farnesoid X-activated receptor
• stearic acid
• Etoposide
• Stearoyl-CoA Desaturase
• Alkaline Phosphatase
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (genetics, metabolism)
• Alkaline Phosphatase (genetics, metabolism)
• Animals
• Blood Vessels (metabolism, pathology)
• Calcinosis (genetics, metabolism, pathology)
• Cattle
• Cells, Cultured
• Etoposide (metabolism)
• Lipogenesis
• Liver X Receptors
• 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)