Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis
| Autor: | Andrew J. Brown, Anika V. Prabhu, Laura J. Sharpe, Winnie Luu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Vitamin Oxidoreductases Acting on CH-CH Group Donors Proteasome Endopeptidase Complex congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty 7-Dehydrocholesterol reductase CHO Cells Reductase Biology Biochemistry 03 medical and health sciences chemistry.chemical_compound 7-Dehydrocholesterol Cricetulus Dehydrocholesterols 0302 clinical medicine Cricetinae Internal medicine medicine Vitamin D and neurology Animals Humans Vitamin D Molecular Biology chemistry.chemical_classification Cholesterol Cell Biology medicine.disease Lipids Smith-Lemli-Opitz Syndrome 030104 developmental biology Enzyme Endocrinology chemistry Smith–Lemli–Opitz syndrome 030220 oncology & carcinogenesis Proteolysis lipids (amino acids peptides and proteins) |
| Zdroj: | Journal of Biological Chemistry. 291:8363-8373 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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