Post-HMG CoA reductase regulation of cholesterol biosynthesis in normal human lymphocytes: Lanosten-3β-ol-32-al, a natural inhibitor

Tabacik, Christiane; Aliau, Sigrid; Serrou, B; Paulet, A. Crastes de

doi:10.1016/0006-291x(81)91559-x

Cited by 43 publications

(10 citation statements)

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“…This may result in increased degradation of HMG-CoA reductase. Whether substances II and III (Scheme 1) play a natural regulatory role in vivo is more controversial, although III accumulates in cells during conditions in which HMG-CoA reductase becomes suppressed (11,40,41). If, as seems One hour before killing, the rats were injected intraperitoneally with 3 H 2 O (4 mCi).…”

Section: Discussionmentioning

confidence: 99%

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Gibbons

2002

Lipids

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A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51, encodes lanosterol 14alpha-demethylase, the first step in the conversion of lanosterol into cholesterol in mammals. The biosynthetic intermediates of lanosterol 14alpha-demethylation are oxysterols, which inhibit HMG-CoA reductase and sterol synthesis in mammalian cells in vitro. These oxysterols (5alpha-lanost-8-en-3beta,32-diol and 3beta-hydroxy-5alpha-lanost-8-en-32-al) are efficiently converted into cholesterol in vitro and are generally considered to be natural cholesterol precursors. When added to hepatocytes in high concentrations, besides their conversion into cholesterol, they are also rapidly metabolized into more polar sterols and into steryl esters. The 15alpha- and 15beta-hydroxy epimers of 5alpha-lanost-8-en-3beta-ol are also rapidly metabolized into more polar sterols and steryl esters but are not converted efficiently into cholesterol. Polar sterol formation from all these oxysterols is dependent on an active form of cytochrome P450. Oxysterols are potent regulators of the activities of transcription factors of the sterol regulatory element-binding protein family and of liver X-receptor alpha. It is proposed that the rapid, cytochrome P450-dependent metabolism of naturally occurring regulatory oxysterols provides a route for their deactivation so that they become incapable of affecting gene transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents the inactivation of such oxysterols, leading to a prolonged suppression of hepatic HMG-CoA reductase in vivo and in vitro.

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Section: Discussionmentioning

confidence: 99%

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Gibbons

2002

Lipids

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“…Accumulation of the CYP51 reaction intermediates (predominantly the 14␣-aldehyde derivative) in vitro is mostly known as a result of nonoptimal reaction conditions (pH, reducing equivalents, inhibitors) that were used in the experiments to elucidate the reaction mechanism (45,46). In vivo, the aldehyde intermediate of the CYP51 reaction was isolated from human tissues and hypothesized to serve as a natural regulator (inhibitor) of sterol biosynthesis (47). We found that the 14␣-aldehyde intermediate is the only compound that can be formed from Lns by the CYP51 ortholog from T. brucei, which we believe might also play a regulatory role in vivo by allowing the bloodstream forms of the parasite to switch the major sterol production from the endogenous carbon source to the usage of the host cholesterol (16).…”

Section: Discussionmentioning

confidence: 99%

Substrate Preferences and Catalytic Parameters Determined by Structural Characteristics of Sterol 14α-Demethylase (CYP51) from Leishmania infantum

Hargrove

Wawrzak

Liu

et al. 2011

Journal of Biological Chemistry

107

129

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Leishmaniasis is a major health problem that affects populations of ϳ90 countries worldwide, with no vaccine and only a few moderately effective drugs. Here we report the structure/ function characterization of sterol 14␣-demethylase (CYP51) from Leishmania infantum. The enzyme catalyzes removal of the 14␣-methyl group from sterol precursors. The reaction is essential for membrane biogenesis and therefore has great potential to become a target for antileishmanial chemotherapy. Although L. infantum CYP51 prefers C4-monomethylated sterol substrates such as C4-norlanosterol and obtusifoliol (V max of ϳ10 and 8 min ؊1 , respectively), it is also found to 14␣-demethylate C4-dimethylated lanosterol (V max ‫؍‬ 0.9 min ؊1 ) and C4-des- These minor structural differences are also likely to underlie CYP51 catalytic rates and drug susceptibility and can be used to design potent and specific inhibitors.

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“…Whereas oxycholesterols exert their affects at the level of transcription, oxylanosterols appear to regulate HMG‐CoA reductase gene expression at the level of translation in cultured cells (80–82). An oxylanosterol, 3β‐hydroxylanost‐8‐en‐32‐al, an intermediate in the 14α demethylation of lanosterol, accumulates when cholesterol biosynthesis is inhibited (83). This compound acts post‐transcriptionally, possibly at the level of translation.…”

Section: Mechanisms Of Feedback Regulationmentioning

confidence: 99%

Feedback and Hormonal Regulation of Hepatic 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase: The Concept of Cholesterol Buffering Capacity

Ness

Chambers

2000

Proc Soc Exp Biol Med

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Abstract. Regulation of the expression of hepatic 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase by the major end product of the biosynthetic pathway, cholesterol, and by various hormones is critical to maintaining constant serum and tissue cholesterol levels in the face of an ever‐changing external environment. The ability to downregulate this enzyme provides a means to buffer the body against the serum cholesterol–raising action of dietary cholesterol. The higher the basal expression of hepatic HMG‐CoA reductase, the greater the “cholesterol buffering capacity” and the greater the resistance to dietary cholesterol. This review focuses on the mechanisms of feedback and hormonal regulation of HMG‐CoA reductase in intact animals rather than in cultured cells and presents the evidence that leads to the proposal that regulation of hepatic HMG‐CoA reductase acts as a cholesterol buffer. Recent studies with animals have shown that feedback regulation of hepatic HMG‐CoA reductase occurs at the level of translation in addition to transcription. The translational efficiency of HMG‐CoA reductase mRNA is diminished through the action of dietary cholesterol. Oxylanosterols appear to be involved in this translational regulation. Feedback regulation by dietary cholesterol does not appear to involve changes in the state of phosphorylation of hepatic HMG‐CoA reductase or in the rate of degradation of this enzyme. Several hormones act to alter the expression of hepatic HMG‐CoA reductase in animals. These include insulin, glucagon, glucocorticoids, thyroid hormone and estrogen. Insulin stimulates HMG‐CoA reductase activity likely by increasing the rate of transcription, whereas glucagon acts by opposing this effect. Hepatic HMG‐CoA reductase activity undergoes a significant diurnal variation due to changes in the level of immunoreactive protein primarily mediated by changes in insulin and glucagon levels. Thyroid hormone increases hepatic HMG‐CoA reductase levels by acting to increase both transcription and stability of the mRNA. Glucocorticoids act to decrease hepatic HMG‐CoA reductase expression by destabilizing reductase mRNA. Estrogen acts to increase hepatic HMG‐CoA reductase activity primarily by stabilizing the mRNA. Deficiencies in those hormones that act to increase hepatic HMG‐CoA reductase gene expression lead to elevations in serum cholesterol levels. High basal expression of hepatic HMG‐CoA reductase, whether due to genetic or hormonal factors, appears to result in greater cholesterol buffering capacity and thus increased resistance to dietary cholesterol.

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Post-HMG CoA reductase regulation of cholesterol biosynthesis in normal human lymphocytes: Lanosten-3β-ol-32-al, a natural inhibitor

Cited by 43 publications

References 10 publications

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Substrate Preferences and Catalytic Parameters Determined by Structural Characteristics of Sterol 14α-Demethylase (CYP51) from Leishmania infantum

Feedback and Hormonal Regulation of Hepatic 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase: The Concept of Cholesterol Buffering Capacity

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