1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

Abstract

Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for five and seven days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)2D treatment for five days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was downregulated with 1,25(OH)2D treatment at two (73%±6 relative to vehicle) and five (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at five days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metabolism in malignant breast epithelial cells.

1α,25(OH)2D3 alleviates high glucose–induced lipid accumulation in rat renal tubular epithelial cells by inhibiting SREBPs

“…Most studies believe that vitamin D prevents lipid accumulation. 12,36,37 In contrast, 1α,25(OH) 2 D 3 treatment increased lipid droplets and cholesterol levels in NRK-52E cells with normal glucose medium in current study. It was a novel finding and inspired us to explore the underlying mechanism.…”

“…Meanwhile, the higher the concentration of 1α,25(OH) 2 D 3 was, the more significant the effect was. Most studies believe that vitamin D prevents lipid accumulation . In contrast, 1α,25(OH) 2 D 3 treatment increased lipid droplets and cholesterol levels in NRK‐52E cells with normal glucose medium in current study.…”

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

“…It has been reported that suppression of the DNL pathway is a potential target for inhibiting cancer cells , and thus, this study speculated that PMCTi might suppress the DNL pathway, which could lead to apoptosis induction in HepG2 cells. We investigated the inhibitory effect of 2.5 m m of the PMCTi for 24 h on the expression of ACLY, ACC, and FASN.…”

Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression

“…Previously, 1,25(OH) 2 D was shown to downregulate PC mRNA and protein expression in metastatic breast cancer cells [31]. PC is a mitochondrial enzyme facilitating the metabolism of pyruvate into OAA.…”