How Does Vitamin D Lower Cholesterol?

Researchers have identified a mechanism by which vitamin D reduces levels of cholesterol. In a mouse study published in the April issue of Gastroenterology, Edwin Chow et al. show that activation of the vitamin D receptor increases cholesterol 7α-hydroxylase (CYP7A1)—an enzyme that metabolizes cholesterol—by downregulating its repressor, SHP.

Vitamin D

Vitamin D

Studies have reported different effects of vitamin D treatment on lipid profiles and cholesterol levels. However, it has not been clear how vitamin D signaling affects cholesterol homeostasis.

Cholesterol is metabolized to bile acids by CYP7A1. In a negative-feedback mechanism, bile acids such as chenodeoxycholic acid activate the farnesoid X receptor (FXR), leading to repression of CYP7A1.

The vitamin D receptor (VDR) binds to its endogenous ligand, 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3) or lithocholic acid (alternate VDR ligand), to activate the transcription of genes.

Chow et al. investigated the interaction between these pathways with various knockout mice given intraperitoneal injections of 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3).

Thee showed that 1,25(OH)2D3 traveled rapidly to the liver, which expressed VDR. There, 1,25(OH)2D3 downregulated the transcriptional repressor SHP, leading to upregulation of CYP7A1. Chromatin immunoprecipitation analysis of livers from mice showed that 1,25(OH)2D3 increased recruitment of VDR and rodent retinoid X receptor to the Shp promoter.

Chow et al. also found that 1,25(OH)2D3 increased expression of CYP7A1 and another VDR target gene, CYP24A1, but reduced Shp mRNA in mouse and human primary hepatocytes.

These findings provide a direct role for VDR in the repression of SHP to upregulate CYP7A1, and a mechanism for reported cholesterol-lowering effects of vitamin D.

Interestingly, Chow et al. observed time-dependent changes in CYP7A1 expression. They say that the involvement of SHP in this pathway might have been previously missed because SHP mRNA has a short half-life (<30 minutes)—it undergoes proteasome degradation, controlled by the extracellular signal-regulated kinase pathway.

The authors propose that the longer-term effects of steady-state doses of 1,25(OH)2D3 that they observed are likely to represent physiologic responses, and that the observed upregulation of CYP7A1 after 1,25(OH)2D3 exposure indicates that the VDR could be a therapeutic target for cholesterol lowering.

However, the utility of this mechanism to treat hypercholesterolemia is limited because 1,25(OH)2D3 and its precursor, 1α-hydroxyvitamin D3, can produce hypercalcemia. Also, it is not clear how dietary vitamin D might be used to lower cholesterol in humans, because only low levels of 1,25(OH)2D3 are synthesized after ingestion. The authors state that vitamin D deficiency could affect cholesterol levels.

Chow et al. propose that the interaction between the VDR and cholesterol homeostasis in humans requires further investigation—especially studies of VDR ligands that do not induce hypercalcemia.

About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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2 Responses to How Does Vitamin D Lower Cholesterol?

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