Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

Sharpe, Laura J.; Brown, Andrew

doi:10.1074/jbc.r113.479808

Cited by 314 publications

(295 citation statements)

References 83 publications

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“…Cholesterol synthesis is controlled at numerous stages (45). DHCR7 inhabits a special place in the pathway, as the gateway to both cholesterol and vitamin D production.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Prabhu

Luu

Sharpe

et al. 2016

Journal of Biological Chemistry

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121

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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.

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“…Cholesterol synthesis is controlled at numerous stages (45). DHCR7 inhabits a special place in the pathway, as the gateway to both cholesterol and vitamin D production.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Prabhu

Luu

Sharpe

et al. 2016

Journal of Biological Chemistry

Self Cite

121

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“…How these later enzymes are regulated is largely unexplored, but there is growing evidence that some of them serve as flux-controlling points (Sharpe and Brown, 2013). In renal cancer cells, for example, another enzyme of the mevalonate pathway, squalene monooxygenase (SM), which converts squalene to squalene-2,3-epoxide (Figure 1), has been proposed as a second rate-limiting enzyme in cholesterol synthesis, and may contribute to renal cancer development (Gonzalez et al, 1979).…”

Section: Cancer-related Regulators Of Cholesterol Metabolismmentioning

confidence: 99%

Cholesterol lowering: role in cancer prevention and treatment

Murai

2014

Biological Chemistry

168

147

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Abstract:The accumulation of cholesterol is a general feature of cancer tissue, and recent evidence suggests that cholesterol plays critical roles in the progression of cancers, including breast, prostate, and colorectal cancers. The dysregulation of metabolic pathways, including those involved in cholesterol biosynthesis, is implicated in tumor development and cancer progression. Lipid rafts are highly dynamic cholesterol-enriched domains of the cell membrane, involved in various cellular functions, including the regulation of transmembrane signaling at the cell surface. It was recently demonstrated that lipid rafts also play critical roles in cancer cell adhesion and migration. This review focuses on our current understanding of how cholesterol regulation, lipid rafts, and dysregulated cholesterol biosynthesis contribute to cancer development and progression, and the therapeutic potential of cholesterol lowering for cancer prevention and treatment.

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“…The lanosterol-to-cholesterol pathway is also complex, involving 19 enzymatic reactions. Lanosterol is either diverted into the Bloch pathway, leading to cholesterol formation through desmosterol, or the Kandutsch-Russell pathway through 7-dehydrocholesterol [43]. Our study indicated that the distal post-squalene sterol metabolites lathosterol, desmosterol and 7-DHC were lower in GT3 patients compared to GT2.…”

Section: Discussionmentioning

confidence: 61%

“…However, the antiviral efficacy of statin monotherapy in HCV patients has proved to be insignificant [41][42]. Regulation of cholesterol synthesis also occurs at other stages in the pathway [43]. The post-squalene pathway distal to HMCoA-R is important in regulation of cholesterol synthesis, and the predominant location of these enzymes in the endoplasmic reticulum also allows for possible interaction with HCV.…”

Section: Discussionmentioning

confidence: 99%

“…The first sterol intermediate is lanosterol formed in a two-step process from the isoprenoid squalene. The first step involves a key enzyme, squalene monooxygenase, which has also been proposed as a second rate limiting enzyme in cholesterol synthesis [43]. The lanosterol-to-cholesterol pathway is also complex, involving 19 enzymatic reactions.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin

Younossi

Stepanova

Estep

et al. 2016

Journal of Hepatology

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Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

Cited by 314 publications

References 83 publications

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Cholesterol lowering: role in cancer prevention and treatment

Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin

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