Tang (2020) Phlorizin ameliorates obesity-associated endotoxemia and insulin resistance in high-fat diet-fed mice by targeting the gut microbiota and intestinal barrier integrity,

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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.

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