Dehydrocholesterol Reductase (DHCR)
Dehydrocholesterol Reductase
Dehydrocholesterol reductases (DHCRs) are critical sterol reductases in the terminal steps of cholesterol biosynthesis; the isoforms DHCR7 and DHCR24 catalyze distinct double-bond reduction reactions and are associated with different hereditary disorders of sterol metabolism. DHCR24 and DHCR7 interact both physically and functionally; knockdown of DHCR24 in cells abolishes DHCR7 activity, whereas overexpression of functional DHCR24 enhances DHCR7 activity, suggesting cooperative regulation at the terminal stage of cholesterol synthesis.
Specifically, DHCR24 (24-dehydrocholesterol reductase) reduces the C24 double bond of sterol intermediates, converting desmosterol into cholesterol; functional deficiency of DHCR24 leads to desmosterol accumulation and causes the autosomal recessive disorder desmosterolosis. DHCR24 inhibitors, such as amiodarone, can directly inhibit the enzyme and promote desmosterol accumulation.
DHCR7 (7-dehydrocholesterol reductase) reduces the Δ7 double bond of 7-dehydrocholesterol (7DHC) to produce cholesterol and serves as the terminal enzyme of the Kandutsch–Russell pathway; functional deficiency of DHCR7 results in 7DHC accumulation and insufficient cholesterol production, constituting the direct genetic and biochemical basis of Smith–Lemli–Opitz syndrome (SLOS).
References:
- [1]. Waterham HR, et al. Mutations in the 3β-hydroxysterol Δ24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet. 2001;69(4):685-694. [Content Brief]
- [2]. Waterham HR, et al. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet. 1998 Aug;63(2):329-38.
- [3]. Simonen P, et al. Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase. J Intern Med. 2020 Nov;288(5):560-569.
- [4]. Prabhu AV, et al. Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis. J Biol Chem. 2016 Apr 15;291(16):8363-73.
- [5]. Luu W, et al. The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally. J Lipid Res. 2015 Apr;56(4):888-97. [Content Brief]
