Increase of circulating cholesterol in vitamin D deficiency is linked to reduced vitamin D receptor activity via the Insig-2/SREBP-2 pathway

• Published in: Molecular nutrition & food research 2016-04, Vol.60 (4), p.798-809
• Main Authors: Li, Songtao, He, Yujie, Lin, Song, Hao, Liuyi, Ye, Yaxin, Lv, Lin, Sun, Zongxiang, Fan, Huiru, Shi, Zhiping, Li, Jie, Feng, Rennan, Na, Lixin, Wang, Yanwen, Li, Ying, Sun, Changhao
• Format: Article
• Language: English
• Subjects: Adult; Animals; Asian Continental Ancestry Group; China; Cholesterol; Cholesterol - blood; Cholesterol - metabolism; Cross-Sectional Studies; Disease Models, Animal; Female; Humans; Insig-2; Intracellular Signaling Peptides and Proteins - metabolism; Male; Membrane Proteins - metabolism; Middle Aged; Rats, Wistar; Receptors, Calcitriol - metabolism; Sterol Regulatory Element Binding Protein 2 - metabolism; Transcriptional activity; Vitamin D - blood; Vitamin D deficiency; Vitamin D Deficiency - blood; Vitamin D Deficiency - metabolism; Vitamin D receptor
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201500425

Scope Individuals deficient in vitamin D are more likely to have higher circulating cholesterol levels and cardiovascular diseases. However, the underlying mechanisms are still unclear. Methods and results A cross‐sectional survey, animal study, and in vitro experiments were conducted to investigate the effect and mechanisms of vitamin D deficiency on endogenous cholesterol metabolism. We demonstrated that vitamin D deficiency was positively associated with an increase of total serum cholesterol and low‐density lipoprotein cholesterol levels in northern Chinese individuals. The vitamin D deficiency‐induced increase of cholesterol concentration was mainly due to enhanced cholesterol biosynthesis rather than reduced catabolism. Under vitamin D deficiency, the transcriptional activity of vitamin D receptor (VDR) was decreased, leading to the downregulation of insulin‐induced gene‐2 (Insig‐2) expression and thus its inhibitory role on sterol regulatory element‐binding protein 2 activation; 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase expression was accordingly increased. Vitamin D3 was protective against vitamin D deficiency‐induced cholesterol increase by maintaining the transcriptional activity of VDR and Insig‐2 expression. Conclusion Vitamin D deficiency is associated with the increase of circulating cholesterol in the people of northern China by enhancing hepatic cholesterol biosynthesis, which was linked to the reduction of transcriptional activity of VDR. Vitamin D deficiency is closely related to cardiovascular diseases. Here, we report that vitamin D deficiency is inversely correlated with total serum cholesterol and low‐density lipoprotein cholesterol levels in north Chinese individuals. A novel hepatic Insig‐2/SREBP‐2/HMGCR pathway might contribute to circulating cholesterol increase. Therefore, sufficient vitamin D3 should be supplemented to prevent such risks.