Sterol 27-hydroxylase: high levels of activity in vascular endothelium.

Reiss, Allison B.; Martin, Kumiko O.; Javitt, Norman B.; Martin, Daniel W.; Grossi, Eugene A.; Galloway, Aubrey C.

doi:10.1016/s0022-2275(20)40099-9

Cited by 85 publications

(18 citation statements)

References 21 publications

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“…Thus it seems likely that not all the 27-hydroxycholesterol that may occur in hepatic mitochondria is further oxidized to the C27 acid but that some undergoes 7 ␣ -hydroxylation prior to further side chain oxidation. This view is consistent with cell culture studies in which 27-hydroxycholesterol appears in the medium before the C27 acid (28), indicating that it is released from the enzyme site before complete oxidation.…”

Section: Overview Of the Cholesterol 27-hydroxylase Metabolic Pathwaysupporting

confidence: 89%

“…Another subcellular route depicted in Fig. 1 derives from the finding that the 27-hydroxylase is widely expressed in tissues (7), including vascular endothelium (28) and macrophages (29). Most of the 27-hydroxycholesterol that is generated is transported in plasma esterified with fatty acids and together with esterified cholesterol is part of LDL and HDL (30).…”

Section: Overview Of the Cholesterol 27-hydroxylase Metabolic Pathwaymentioning

confidence: 99%

“…Both monohydroxy bile acids normally circulate in plasma in nanomolar amounts, but only the latter has been reported in amniotic fluid, meconium, bile, and urine (39)(40)(41)(42). Presumably the C27 acid undergoes further oxidation to the C24 acid in peroxisomes, perhaps exclusively in the liver, since the C24 acid was not identified as a metabolite when 27-hydroxycholesterol was incubated with nonhepatic tissues (28).…”

Section: Monohydroxy Bile Acid Synthesismentioning

confidence: 99%

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25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles

Javitt

2002

Journal of Lipid Research

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The CYP27 gene is expressed in arterial endothelium, macrophages, and other tissues. The gene product generates sterol intermediates that function as ligands for nuclear receptors prior to their transport to the liver for metabolism, mostly to bile acids. Most attention has been given to 27-hydroxycholesterol as a ligand for LXR activated receptors and to chenodeoxycholic acid as a ligand for farnesoid X activated receptors (FXRs). Expression of the pathway in macrophages is essential for normal reverse cholesterol transport. Thus, ABC transporter activity is upregulated, which enhances cholesterol efflux. Absence of these mechanisms probably accounts for the accelerated atherosclerosis that occurs in cerebrotendinous xanthomatosis. Accumulation of 27-hydroxycholesterol in human atheroma is puzzling and may reflect low levels of oxysterol 7 ␣hydroxylase activity in human macrophages. The same enzyme determines the proportion of mono-, di-, and trihydroxy bile acids synthesized in the liver. Oxysterol 7 ␣hydroxylase deficiency is a molecular basis for cholestatic liver disease. Chenodeoxycholic acid, the major normal end product, downregulates expression of cholesterol 7 ␣ -hydroxylase via the FXR/short heterodimer protein nuclear receptor and thus limits total bile acid production.The challenge is to quantify in a physiologic setting the magnitude of the pathway in different tissues and to further evaluate the biologic roles of all the intermediates that may function as ligands for orphan nuclear receptors or via other regulatory mechanisms. -Javitt, N. B. 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles.

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Section: Overview Of the Cholesterol 27-hydroxylase Metabolic Pathwaysupporting

confidence: 89%

Section: Overview Of the Cholesterol 27-hydroxylase Metabolic Pathwaymentioning

confidence: 99%

Section: Monohydroxy Bile Acid Synthesismentioning

confidence: 99%

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25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles

Javitt

2002

Journal of Lipid Research

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“…16 Immune complexes acting through a C1q receptor protein also inhibit the enzyme cholesterol 27-hydroxylase, which is expressed in arterial endothelium and monocyte/macrophage cell lines. 17 This enzyme catalyses hydroxylation of cholesterol to 27-hydroxycholesterol. This is more water soluble and easily removed from the arterial wall as part of reverse cholesterol transport.…”

Section: Inflammatory Mechanismsmentioning

confidence: 99%

Atherogenesis and autoimmune disease: the model of lupus

Bruce

2005

Lupus

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Accelerated atherosclerosis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Certain 'classic' risk factors are associated with atherosclerosis risk in SLE. However, these factors alone do not fully explain the excess risk observed. Atherosclerosis is increasingly recognized as a chronic inflammatory condition and in SLE, complement activation and immune complex formation may promote atheroma development. Similarly, autoantibody production, especially those in the anticardiolipin (ACLA) family are gaining increasing attention. The role of steroids may not be completely straightforward, low doses may have a beneficial anti-inflammatory role whereas higher doses may exacerbate metabolic factors. In contrast, antimalarials have a beneficial effect on lipids as well as anti-inflammatory and anti-platelet effects. The aetiology of atherosclerosis in SLE is therefore multifactorial. A better understanding of the interface of autoimmunity and atherogenesis in the context of SLE will benefit lupus patients and will also help us better understand the pathogenesis of atherosclerosis in general.

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“…It has recently been appreciated that the metabolism of cholesterol to 27-hydroxycholesterol by endothelial cells and macrophages in the arterial wall by the action of the mitochondrial P450 enzyme cholesterol 27-hydroxylase may constitute one of the first lines of defense in the prevention of atherosclerosis (8)(9)(10)(11)(12). Cholesterol 27-hydroxylase catalyzes the first step in the extrahepatic metabolism of cholesterol.…”

mentioning

confidence: 99%

Immune complexes and IFN-γ decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages

Reiss

Awadallah

Malhotra

et al. 2001

Journal of Lipid Research

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The enzyme cholesterol 27-hydroxylase, expressed by arterial endothelium and monocytes/macrophages, is one of the first lines of defense against the development of atherosclerosis. By catalyzing the hydroxylation of cholesterol to 27-hydroxycholesterol, which is more soluble in aqueous medium, the enzyme promotes the removal of cholesterol from the arterial wall. Prior studies have suggested that immune reactants play a role in the pathogenesis of atherosclerosis; we report here that immune reactants, IFN-␥ and immune complexes bound to C1q, but not interleukin-1 and tumor necrosis factor, diminish the expression of cholesterol 27-hydroxylase in human aortic endothelial cells, peripheral blood mononuclear cells, monocyte-derived macrophages, and the human monocytoid cell line THP-1. In addition, our studies demonstrate that immune complexes down-regulate cholesterol 27-hydroxylase only after complement fixation via interaction with the 126-kD C1qRp protein on endothelial cells and THP-1 cells. These results are consistent with the prior demonstration that IFN-␥ contributes to the pathogenesis of atherosclerosis and suggest a role for C1q receptors in the atherogenic process. Moreover, these observations suggest that one mechanism by which immune reactants contribute to the development of atherosclerosis is by down-regulating the expression of the enzymes required to maintain cholesterol homeostasis in the arterial wall. -Reiss, A

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Sterol 27-hydroxylase: high levels of activity in vascular endothelium.

Cited by 85 publications

References 21 publications

25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles

25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles

Atherogenesis and autoimmune disease: the model of lupus

Immune complexes and IFN-γ decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages

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