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.

Vitamin D Metabolism Revised: Fall of Dogmas

“…The regulation of DHCR7 is incompletely understood. Cholesterol and vitamin D (but not 1,25(OH) 2 D) increase proteasomal degradation of DHCR7, as does UVB, leading to increased vitamin D production . AMPK, a key sensor and regulator of cellular energy homeostasis, and protein kinase A are potent inhibitors of DHCR7, whereas CaMKII has a lower inhibitory effect .…”

“…Cholesterol and vitamin D (but not 1,25(OH) 2 D) increase proteasomal degradation of DHCR7, as does UVB, leading to increased vitamin D production. (30) AMPK, a key sensor and regulator of cellular energy homeostasis, and protein kinase A are potent inhibitors of DHCR7, whereas CaMKII has a lower inhibitory effect. (31,32) Most textbooks and reviews clearly state that the photochemical production of vitamin D in the skin is a nonenzymatic reaction.…”

Proteostatic Tactics in the Strategy of Sterol Regulation

“…Thus, clinical approaches for this currently incurable disease include ways to elevate DHCR7 levels in patients. Recent work (e.g., by Prabhu et al 2016) indicated that DHCR7 is subject to cholesterol-regulated degradation. Elevating the level of cholesterol in cultured mammalian cells causes selective degradation by the proteasome.…”

Routes and mechanisms of post‐endosomal cholesterol trafficking: A story that never ends

“…When cholesterol in the ER exceeds 5 mole% of total ER lipids, the ER‐to‐Golgi transport of the SREBP/SCAP complex is rapidly blocked, preventing the transcription of genes involved in cholesterol biosynthesis and uptake . High level of cholesterol in ER membranes also accelerates the proteasomal degradation of key enzymes of cholesterol biosynthetic pathway, such as 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR), squalene monooxygenase and 7‐dehydrocholesterol reductase . In addition, excess free cholesterol activates ACAT allosterically, resulting in the production of cholesteryl esters that are stored together with triacylglycerols in the lipid droplets …”

“…57,58 High level of cholesterol in ER membranes also accelerates the proteasomal degradation of key enzymes of cholesterol biosynthetic pathway, such as 3hydroxy-3-methylglutaryl-CoA reductase (HMGCR), 59,60 squalene monooxygenase 61 and 7-dehydrocholesterol reductase. 62 In addition, excess free cholesterol activates ACAT allosterically, resulting in the production of cholesteryl esters that are stored together with triacylglycerols in the lipid droplets. 63,64 While LDL-cholesterol can reach the ER by vesicular trafficking, most likely through the trans-Golgi network (TGN) (as discussed later), there has been increasing appreciation that the tubular ER network is closely apposed to almost all LEs in the cell.…”