Subcellular localization of sterol biosynthesis enzymes
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Cholesterol synthesis is a complex, coordinated process involving a series of enzymes. As of today, our understanding of subcellular localization of cholesterol biosynthesis enzymes is far from complete. Considering the complexity and intricacies of this pathway and the importance of functions of DHCR7, DHCR24 and EBP enzymes for human health, we undertook a study to determine their subcellular localization and co-localization. Using expression constructs and antibody staining in cell cultures and transgenic mice, we found that all three enzymes are expressed in ER and nuclear envelope. However, their co-localization was considerably different across the cellular compartments. Furthermore, we observed that in the absence of DHCR7 protein, DHCR24 shows a compensatory upregulation in a Dhcr7−/− transgenic mouse model. The overall findings suggest that the sterol biosynthesis enzymes might not always work in a same functional complex, but that they potentially have different, multifunctional roles that go beyond the sterol biosynthesis pathway. Furthermore, the newly uncovered compensatory mechanism between DHCR7 and DHCR24 could be of importance for designing medications that would improve cholesterol production in patients with desmosterolosis and Smith–Lemli–Opitz syndrome.
KeywordsDHCR7 EBP DHCR24 7-Dehydrocholesterol 8-Dehydrocholesterol Desmosterol
This work was supported by The National Institutes of Health, NIMH MH110636 (KM) and MN067234 (KM). Katalin Koczok was the Rosztoczy Foundation scholar.
- Batta AK, Tint GS, Shefer S, Abuelo D, Salen G (1995) Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith–Lemli–Opitz syndrome. J Lipid Res 36:705–713Google Scholar
- Jiang XS, Backlund PS, Wassif CA, Yergey AL, Porter FD (2010) Quantitative proteomics analysis of inborn errors of cholesterol synthesis: identification of altered metabolic pathways in DHCR7 and SC5D deficiency. Mol Cell Proteomics 9:1461–1475. https://doi.org/10.1074/mcp.M900548-MCP200 CrossRefGoogle Scholar
- Kandutsch AA, Russell AE (1960) Preputial gland tumor sterols. 3. A metabolic pathway from lanosterol to cholesterol. J Biol Chem 235:2256–2261Google Scholar
- Paik YK, Billheimer JT, Magolda RL, Gaylor JL (1986) Microsomal enzymes of cholesterol biosynthesis from lanosterol. Solubilization and purification of steroid 8-isomerase. J Biol Chem 261:6470–6477Google Scholar
- Rittenberg D, Borek E, Bloch K (1946) Synthesis of cholesterol in liver slices. Fed Proc 5:151Google Scholar