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Cholesterol‐Mediated Degradation of 7‐Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis
Author(s) -
Sharpe Laura Jane,
Prabhu Anika Vinayak,
Luu Winnie,
Brown Andrew John
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1064.1
Subject(s) - smith–lemli–opitz syndrome , cholesterol , reductase , 7 dehydrocholesterol reductase , cholesterol synthesis , enzyme , chemistry , hmg coa reductase , vitamin , medicine , endocrinology , biochemistry , biology
Cholesterol is essential for normal embryogenesis, but in excess, it can be detrimental to human health. To achieve balanced cholesterol levels, enzymes involved in its synthesis possess many layers of regulation. Here, we investigated the post‐translational regulation of 7‐dehydrocholesterol reductase (DHCR7), a terminal enzyme of cholesterol synthesis, converting 7‐dehydrocholesterol to cholesterol. In the absence of functional DHCR7, accumulation of 7‐dehydrocholesterol and a lack of cholesterol production leads to the devastating developmental disorder, Smith‐Lemli‐Opitz Syndrome (SLOS). We found that statin treatment can ameliorate the low DHCR7 expression observed with common SLOS mutants. Furthermore, we show that DHCR7 protein is rapidly turned over and this degradation is induced by the cholesterol product itself, resulting in decreased DHCR7 protein levels and activity. The loss of enzymatic activity results in the accumulation of the substrate 7‐dehydrocholesterol, which in turn leads to an increased production of vitamin D. Thus, DHCR7 is an important enzymatic switch between cholesterol and vitamin D synthesis. Support or Funding Information National Health and Medical Research Council Grant (1060515), UNSW Goldstar Award, UNSW Career Advancement Fund