title: Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis.
abstract: Cholesterol is detrimental to human health in excess but is also essential for normal embryogenesis. Hence, enzymes involved in its synthesis possess many layers of regulation to achieve balanced cholesterol levels. 7-Dehydrocholesterol reductase (DHCR7) is the terminal enzyme of cholesterol synthesis in the Kandutsch-Russell pathway, converting 7-dehydrocholesterol (7DHC) to cholesterol. In the absence of functional DHCR7, accumulation of 7DHC and a lack of cholesterol production leads to the devastating developmental disorder, Smith-Lemli-Opitz syndrome. This study identifies that statin treatment can ameliorate the low DHCR7 expression seen with common Smith-Lemli-Opitz syndrome mutations. Furthermore, we show that wild-type DHCR7 is also relatively labile. In an example of end-product inhibition, cholesterol accelerates the proteasomal degradation of DHCR7, resulting in decreased protein levels and activity. The loss of enzymatic activity results in the accumulation of the substrate 7DHC, which leads to an increased production of vitamin D. Thus, these findings highlight DHCR7 as an important regulatory switch between cholesterol and vitamin D synthesis.
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Anika V
authors.initials: AV
authors.lastname: Prabhu
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Winnie
authors.initials: W
authors.lastname: Luu
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sharpe
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia aj.brown@unsw.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003684:Dehydrocholesterols / Q000378:metabolism*; D006801:Humans; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D019082:Smith-Lemli-Opitz Syndrome / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014807:Vitamin D / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D003684:Dehydrocholesterols; D014807:Vitamin D; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D046988:Proteasome Endopeptidase Complex
keywords: 7-dehydrocholesterol; DHCR7; cholesterol; cholesterol regulation; enzyme degradation; genetic disease; vitamin D