Dr. Ron’s Research Review – August 19, 2020

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This week’s research review focuses on Vitamin D and cholesterol.

7-Dehydrocholesterol Reductase

The conversion of 7-dehydrocholesterol to cholesterol is catalyzed by 7-dehydrocholesterol reductase (DHCR7). 7-dehydrocholesterol is also a precursor of vitamin D via the action of ultraviolet light on the skin. DHCR7 may act as a switch between cholesterol and vitamin D synthesis. (Prabhu et al., 2016)

UV Light

A study found that UV light increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol. (Shin et al., 2019)

Vitamin D and Lipid Profile

A study found that high serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile. (Jorde et al., 2010)
The study was performed at the University of Tromsø, Northern Norway. In total, 8018 nonsmoking and 2087 smoking subjects were included in a cross-sectional study performed in 2008, and 1762 nonsmoking and 397 smoking subjects in a longitudinal study. Nonfasting serum 25(OH)D, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio and triacylglycerol (TAG) were measured.
After adjustment for gender, age, sample month and body mass index in the cross-sectional study, there was a significant increase in serum TC, HDL-C and LDL-C, and a significant decrease in serum LDL-C/HDL-C ratio and TAG across increasing serum 25(OH)D quartiles. For serum HDL-C and TAG in nonsmokers the differences between the means for the highest and lowest serum 25(OH)D quartiles were 6.0 and 18.5%, respectively. In the longitudinal study, an increase in serum 25(OH)D was associated with a significant decrease in serum TAG.
There is a cross-sectional association between serum 25(OH)D and serum lipids, and a longitudinal association over 14 years between serum 25(OH)D and TAG, which may contribute to explain the relation between low serum 25(OH)D concentrations and mortality.

Dr. Ron


Articles

 

High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile.
            (Jorde et al., 2010)  Download
BACKGROUND/OBJECTIVES:  Low serum 25-hydroxyvitamin D (25(OH)D) concentrations are related to increased mortality. One possible explanation could be an association between serum 25(OH)D and serum lipids. SUBJECTS/METHODS:  The study was performed at the University of Tromsø, Northern Norway. In total, 8018 nonsmoking and 2087 smoking subjects were included in a cross-sectional study performed in 2008, and 1762 nonsmoking and 397 smoking subjects in a longitudinal study from 1994/1995 to 2008. Nonfasting serum 25(OH)D, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio and triacylglycerol (TAG) were measured. RESULTS:  After adjustment for gender, age, sample month and body mass index in the cross-sectional study, there was a significant increase in serum TC, HDL-C and LDL-C, and a significant decrease in serum LDL-C/HDL-C ratio and TAG across increasing serum 25(OH)D quartiles. For serum HDL-C and TAG in nonsmokers the differences between the means for the highest and lowest serum 25(OH)D quartiles were 6.0 and 18.5%, respectively. In the longitudinal study, an increase in serum 25(OH)D was associated with a significant decrease in serum TAG. CONCLUSIONS:  There is a cross-sectional association between serum 25(OH)D and serum lipids, and a longitudinal association over 14 years between serum 25(OH)D and TAG, which may contribute to explain the relation between low serum 25(OH)D concentrations and mortality.

DHCR7: A vital enzyme switch between cholesterol and vitamin D production.
            (Prabhu et al., 2016)  Download
The conversion of 7-dehydrocholesterol to cholesterol, the final step of cholesterol synthesis in the Kandutsch-Russell pathway, is catalyzed by the enzyme 7-dehydrocholesterol reductase (DHCR7). Homozygous or compound heterozygous mutations in DHCR7 lead to the developmental disease Smith-Lemli-Opitz syndrome, which can also result in fetal mortality, highlighting the importance of this enzyme in human development and survival. Besides serving as a substrate for DHCR7, 7-dehydrocholesterol is also a precursor of vitamin D via the action of ultraviolet light on the skin. Thus, DHCR7 exerts complex biological effects, involved in both cholesterol and vitamin D production. Indeed, we argue that DHCR7 can act as a switch between cholesterol and vitamin D synthesis. This review summarizes current knowledge about the critical enzyme DHCR7, highlighting recent findings regarding its structure, transcriptional and post-transcriptional regulation, and its links to vitamin D synthesis. Greater understanding about DHCR7 function, regulation and its place within cellular metabolism will provide important insights into its biological roles.

 

UV increases skin-derived 1α,25-dihydroxyvitamin D|3| production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol.
            (Shin et al., 2019)  Download
The skin is a unique site in the human body that has the capacity to synthesize the active form of vitamin D, 1α,25-dihydroxyvitamin D|3| (1α,25(OH)|2|D|3|), from 7-dehydrocholesterol (7DHC) upon UV irradiation. Keratinocytes express both 25-hydroxylase (CYP27A1 and CYP2R1) and 1α-hydroxylase (CYP27B1), critical enzymes involved in active vitamin D synthesis. Here, we investigated the effect of skin-derived 1α,25(OH)|2|D|3|, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH)|2|D|3,| but not 7DHC or 25OHD|3|, significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH)|2|D|3| levels, and ketoconazole inhibits UV-induced production of 1α,25(OH)|2|D|3|. Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH)|2|D|3| synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH)|2|D|3| synthesis. We demonstrated that UV irradiation leads to decreased expression of DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts 7DHC to cholesterol. Inhibition of DHCR7 with its inhibitor BM15766 decreased cholesterol synthesis and increased UV-induced MMP-1 expression, which was attenuated by ketoconazole. These findings suggest that UV-induced reduction of DHCR7 leads to a decrease in cholesterol synthesis, thereby increasing 7DHC availability for 1α,25(OH)|2|D|3| production, which enhances MMP-1 expression. Finally, UV irradiation in human skin in vivo significantly increased CYP27B1 mRNA and decreased DHCR7 mRNA expression. Taken together, we demonstrate here that skin-derived 1α,25(OH)|2|D|3| significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH)|2|D|3.| Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH)|2|D|3| synthesis, but downregulates the cholesterol-producing enzyme DHCR7, both of which collectively lead to increased MMP-1 expression in human keratinocytes. This pathway may be exploited to develop a novel cutaneous anti-aging agent that blocks local cutaneous 1α,25(OH)|2|D|3| synthesis.

 


 

References

Jorde, R, et al. (2010), ‘High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile.’, Eur J Clin Nutr, 64 (12), 1457-64. PubMed: 20823896
Prabhu, AV, et al. (2016), ‘DHCR7: A vital enzyme switch between cholesterol and vitamin D production.’, Prog Lipid Res, 64 138-51. PubMed: 27697512
Shin, MH, et al. (2019), ‘UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol.’, J Steroid Biochem Mol Biol, 195 105449. PubMed: 31470109