Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine

Abstract

Objective Prevalence of vitamin D-deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of vitamin D status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine. Approach and Results Yucatan microswine were fed with vitamin D-deficient (0IU/d), vitamin D-sufficient (1,000IU/d) or vitamin D-supplemented (3,000IU/d) high cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)2D3 on cholesterol metabolism was examined in human HepG2 and THP-1 macrophage-derived foam cells. Vitamin D-deficiency decreased plasma HDL levels, expression of liver-X-receptors (LXRs), ATP binding cassette transporter A1 (ABCA1) and ABCG1, and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. Vitamin D promoted nascent HDL formation in HepG2 cells via ABCA1-mediated cholesterol efflux. CYP27B1 and VDR were predominantly present in the CD206 + M2 macrophage foam cell-accumulated cores in coronary artery plaques. 1,25(OH)2D3 increased the expression of LXRs, ABCA1, ABCG1, and promoted cholesterol efflux in THP-1 macrophage-derived foam cells. 1,25(OH)2D3 decreased intracellular free cholesterol and polarized macrophages to M2-phenotype with decreased expression of TNF-α, IL-1β, IL-6 under LPS-stimulation. 1,25(OH)2D3 markedly induced CYP27A1 expression via a VDR-dependent JNK1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced LXRs, ABCA1 and ABCG1 expression, stimulated cholesterol efflux that was inhibited by VDR antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage-derived foam cell. Conclusion Vitamin D protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.

Reactive Oxygen Species Generation and Atherosclerosis

“…83 In the atherosclerotic lesions, macrophages ingest oxidized LDL through scavenger receptors and become lipid-laden foam cells. 85 Under prolonged ER stress and extracellular stimuli, foam cells eventually undergo apoptosis and lead to the development of atherosclerosis. Although it has been well established that oxidative stress is involved in regulating monocyte migration, differentiation, and macrophage functions in atherosclerosis, [86][87][88] its origins and regulation in this process remain poorly understood.…”

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…113 At least as observed in animal models, vitamin D (mainly through its VDR) exerts a fundamental role on macrophage activity and polarization, particularly in their ability to respond to injury causing an inflammatory reaction. [114][115][116] The inhibitory activity of vitamin D toward inflammation has a role in counteracting adverse effects caused by the inflammatory response.…”

Associations between abnormal vitamin D metabolism pathway function and non‑small cell lung cancer

“…However, the identification of specific biomarkers for the early diagnosis and prognosis of lung cancer is still required (17). The most bioactive metabolite of vitamin D, 1α,25(OH) 2 D 3 has been confirmed to contribute various non-endocrine functions in addition to maintaining calcium stability; including anti-proliferative activity, induction of cell differentiation, promotion of cell cycle stagnation and apoptosis, inhibiting cytopoiesis and regulating tumor occurrence and development (18,19). Vitamin D generates 1α,25(OH) 2 CYP27A1, CYP27B1, and CYP24A1 belong to the cytochrome P450 (CYP450) family.…”