Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells

Xu, Libin; Korade, Željka; Rosado, Dale A.; Mirnics, Károly; Porter, Ned A.

doi:10.1194/jlr.m035733

Cited by 49 publications

(67 citation statements)

References 36 publications

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“…On the other hand, the endoperoxyenone (from addition at C5 or C9) formed in Scheme 7C was found to be unstable and was further reduced by α-tocopherol to give 3β,5α,9α-trihydroxycholest-7-en-6-one ( THCEO ), which can further dehydrate at C9 and C11 to give 3β,5α-dihydroxycholesta-7,9(11)-dien-6-one ( DHCDO ). Notably, all three enones discussed here have been identified in the brain of a mouse model for SLOS [23,24]. …”

Section: Mechanisms Of Sterol Oxidation and The Effect Of α-Tocopheromentioning

confidence: 99%

“…We define the oxysterols formed from free radical oxidation of 7-DHC in solution as the primary oxysterols since they are not metabolized in a biological environment [23]. Upon analysis of samples from cell and animal models for SLOS, the oxysterol profiles in the SLOS samples are distinctly different from the profile found in solution oxidations [19,20,22].…”

Section: Biological Consequences Of 7-dhc-derived Oxysterols and Theimentioning

confidence: 99%

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Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

Porter

2014

Free Radical Research

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Free radical oxidation of cholesterol and its precursors contribute significantly to the pathophysiology of a number of human diseases. This review intends to summarize recent developments and provide a perspective on the reactivities of sterols toward free radical oxidation, the free radical reaction mechanism, and the biological consequences of oxysterols derived from the highly oxidizable cholesterol precursor, 7-dehydrocholesterol. We propose that the rigid structures, additional substituents on the double bonds, and the well-aligned reactive C–H bonds in sterols make them more prone to free radical oxidation than their acyclic analogs found in unsaturated fatty acids. The mechanism of sterol peroxidation follows some well-established reaction pathways found in the free radical peroxidation of polyunsaturated fatty acids, but sterols also undergo some reactions that are unique to these compounds. Peroxidation of 7-dehydrocholesterol gives arguably the most diverse set of oxysterol products that have been observed to date. The metabolism of these oxysterols in cells and the biological consequences of their formation will be discussed in the context of the pathophysiology of the human disease Smith–Lemli–Opitz syndrome. Considering the high reactivity of sterols, we propose that a number of other cholesterol biosynthesis disorders may be associated with oxidative stress.

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Section: Mechanisms Of Sterol Oxidation and The Effect Of α-Tocopheromentioning

confidence: 99%

Section: Biological Consequences Of 7-dhc-derived Oxysterols and Theimentioning

confidence: 99%

Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

Porter

2014

Free Radical Research

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“…4B). One of these, another endoperoxide compound referred to as 2a (5α,9α-epidioxycholest-7-en-3β,6α-diol), does not accumulate in cells and tissues due to its rapid metabolism (35) and is likely not the endogenous inhibitory sterol. Importantly, compound 2b, which is the 6β-hydroxy isomer of compound 2a, did not show inhibitory activity (Fig.…”

Section: Ergosterol Endoperoxide Isolated From Chlamydomonas Reinhardtiimentioning

confidence: 99%

Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols

Sever

Mann

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith–Lemli–Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-β-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3β,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith–Lemli–Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.

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“…Interestingly, the levels of 7-ketocholesterol correlated with the severity score of the SLO. The possibility that this steroid is formed ex vivo from 7-dehydrocholesterol was clearly excluded and 7-ketocholesterol is not among the products formed from 7-dehydrocholesterol under conditions of lipid peroxidation ( 15 ), although it is from cholesterol by ex vivo oxidation. The possibility was discussed that the elevated levels of 7-ketocholesterol in patients with SLO may be formed by the above CYP7A1-mediated mechanism.…”

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confidence: 99%

On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO

Björkhem

Diczfalusy

Lövgren‐Sandblom

et al. 2014

Journal of Lipid Research

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Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells

Cited by 49 publications

References 36 publications

Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols

On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO

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