Importance of a Novel Oxidative Mechanism for Elimination of Intracellular Cholesterol in Humans

Lund, Erik; Andersson, Olof; Zhang, Jie; Babiker, Amir; Ahlborg, Gunvor; Diczfalusy, Ulf; Einarsson, Kurt; Sjövall, Jan; Björkhem, Ingemar

doi:10.1161/01.atv.16.2.208

Cited by 152 publications

(130 citation statements)

References 19 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…45 Interestingly, the 27-hydroxylase pathway has been suggested to be important in the removal of extrahepatic cholesterol. 46 As the accumulation of cholesterol preceded that of 27HC, the formation of the latter may be interpreted as a physiological (potentially anti-atherogenic) response to cholesterol load.…”

Section: Discussionmentioning

confidence: 99%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

126

View full text Add to dashboard Cite

Oxidative modification of low-density lipoprotein is thought to promote arterial lipid accumulation and atherogenesis. Previous studies reported on the presence of certain lipid or protein oxidation products in lesions, although a systematic investigation measuring several oxidation parameters and the accumulation of nonoxidized lipids and antioxidants at various stages of atherosclerosis has not been performed in the same tissue. Using the intimal lipoprotein-containing fraction of human aortic lesions, we demonstrate here that cholesterol accumulated with lesion development and that this increase was already significant at the fatty streak stage. By comparison, cholesterylesters increased significantly only in fibrofatty and more complex lesions that also contained significantly increased amounts of cholesterylester hydro(pero)xides and 27-hydroxycholesterol. Cholesterylester hydroxides were the major lipid oxidation product detected. Despite accumulation of oxidized lipid, ␣-tocopherol was also present and maintained at a comparable level over the disease process. Of the oxidized protein moieties measured only o,o-dityrosine increased with disease, although chlorotyrosines were present at relatively high levels in all lesions compared to healthy vessels. Our data show that accumulation of nonoxidized lipid precedes that of oxidized lipid in human aortic lesions. The development of atherosclerosis to clinical manifestations is a protracted process that spans several decades. It is well established that lipids, specifically cholesterol, accumulate as the disease progresses 1 and that these lipids are derived from plasma low-density lipoprotein (LDL). Aberrant uptake of LDL and its associated lipids by intimal monocytes that have infiltrated from the blood is believed to generate foam cells and thereby initiate atherosclerosis. 2 Foam cells are the hallmark of the fatty streak/early lesion from which the more advanced and complicated lesions derive. In advanced lesions, a fibrous cap is formed from collagen and a lipid-rich necrotic core. Vessel lumen narrowing because of the enlarged fibrous cap and plaque rupture lead to clinical manifestations.The definitive mechanisms leading to the initiation and development of atherosclerosis are unknown. However, retention of LDL in the vessel wall because of interaction and complex formation with extracellular matrix components is well-documented 3 and is thought to be important. Further, a bulk of evidence suggests that oxidative modifications to LDL contribute to its retention. 4 -6 Both arterial wall retention and oxidative modification of LDL are thought to contribute to foam cell formation.In vitro studies with plasma LDL have shown that oxidative modifications proceed in different stages and involve changes to LDL's antioxidants, lipids, and protein components. The nature and extent of these alterations vary depending on the type of oxidant involved, the oxidant to lipoprotein ratio used, and the extent to which oxidation is allowed to proceed. Originally 4 the pa...

show abstract

Section: Discussionmentioning

confidence: 99%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

126

View full text Add to dashboard Cite

show abstract

“…This oxidative mechanism has the potential to eliminate up to about half of the content of cholesterol in the cultured cells in 24 h. Both the alcohol and the acid are primary products of the sterol 27-hydroxylase, and 3␤-hydroxy-5-cholestenoic acid is thus formed by three consecutive hydroxylations at the same methyl group (2). We have also demonstrated that there is a continuous net flux of 27-oxygenated products to the liver, where these metabolites are efficiently converted into bile acids (3). It was shown that up to 4% of the total formation of bile acids in humans may occur by a mechanism involving extrahepatic 27-hydroxylation of cholesterol (3).…”

mentioning

confidence: 83%

“…We have also demonstrated that there is a continuous net flux of 27-oxygenated products to the liver, where these metabolites are efficiently converted into bile acids (3). It was shown that up to 4% of the total formation of bile acids in humans may occur by a mechanism involving extrahepatic 27-hydroxylation of cholesterol (3).…”

mentioning

confidence: 83%

Elimination of Cholesterol in Macrophages and Endothelial Cells by the Sterol 27-Hydroxylase Mechanism

Babiker

Andersson

Lund

et al. 1997

Journal of Biological Chemistry

Self Cite

220

165

View full text Add to dashboard Cite

Cultured macrophages and endothelial cells have been reported to secrete 27-oxygenated metabolites of cholesterol. This mechanism was compared with the classical high density lipoprotein (HDL)-dependent reverse cholesterol transport. Under standard conditions, macrophage preparations had considerably higher capacity to secrete 27-hydroxycholesterol and 3␤-hydroxy-5-cholestenoic acid than had endothelial cells and fibroblasts. Western blotting showed that lung macrophages contained the most sterol 27-hydroxylase protein of the cells tested. The relative amounts of 3␤-hydroxy-5-cholestenoic acid produced by the macrophages were also highest. Macrophages derived from monocytes of patients with sterol 27-hydroxylase deficiency did not secrete 27-oxygenated products, demonstrating that sterol 27-hydroxylase is the critical enzyme for the conversion of cholesterol into the 27-oxygenated steroids. That sterol 27-hydroxylase is responsible not only for 27-hydroxylation of cholesterol but also for the further oxidation of this steroid into 3␤-hydroxy-5-cholestenoic acid was shown with use of tritium-labeled 27-hydroxycholesterol and an inhibitor of sterol 27-hydroxylase.Secretion of 27-oxygenated products by the cultured macrophages as well as the ratio between the alcohol and the acid appeared to be dependent upon total 27-hydroxylase activity, the availability of substrate cholesterol, and the presence of an acceptor for 27-hydroxycholesterol in the medium. With albumin as extracellular acceptor, the major secreted product was 3␤-hydroxy-5-cholestenoic acid. Under such conditions, secretion of labeled 27-oxygenated products was higher than that of labeled cholesterol from lung alveolar macrophages preloaded with [4-14 C]cholesterol. With HDL as acceptor, 27-hydroxycholesterol was the major secreted product, and the total secretion of labeled 27-oxygenated products was only about 10% of that of labeled cholesterol. Thus, 27-hydroxycholesterol and cholesterol may compete for HDL-mediated efflux from the cells.The results support the contention that the sterol 27-hydroxylase-mediated elimination of cholesterol is more important in macrophages than in endothelial cells. This mechanism may be an alternative and/or a complement to the classical HDL-mediated reverse cholesterol transport in macrophages, in particular when the concentration of HDL is low.

show abstract

“…In the CID spectrum of [16,16,17(or 20) ] isotopomer and glycine conjugate, and also 3␤,7␣-dihydroxychol-5-en-24-oic acid, were oxidized with cholesterol oxidase, reacted with GP hydrazine, and analyzed by ES mass spectrometry. Oxidation of these bile acids with cholesterol oxidase results in conversion of the 3␤-hydroxyl group to a ketone, and movement of the ⌬ 5(6) double-bond to ⌬ 4 (5) . In this translocation one of the deuterium atoms on C-4 of the deuterated isotopomers is lost to give a mass increase overall of 4 Da (i.e., [ In the low mass range of the spectrum, the usual pattern of fragment ions at m/z 80.05, 94.07, 108.08, 109.08, 120.05/120.08 and 137.07 is distorted by the presence of ions at m/z 81.07 and 99.08.…”

Section: Group (Iii) Fragment Ions: Gp Hydrazone Neutral-loss Fragmenmentioning

confidence: 99%

“…However, other oxysterols are intermediates in the formation of steroid hormones. Oxysterol formation can occur in many tissues and organs, and conversion of an oxysterol to a bile acid is not restricted to the liver [3][4][5][6][7]. Hormonally active steroids can also be synthesized from cholesterol outside the endocrine organs.…”

mentioning

confidence: 99%

Analysis of oxysterols by electrospray tandem mass spectrometry

Griffiths

Wang

Alvélius

et al. 2006

J. Am. Soc. Mass Spectrom.

104

102

View full text Add to dashboard Cite

Oxysterols are oxygenated derivatives of cholesterol. They are intermediates in cholesterol excretion pathways and may also be regarded as transport forms of cholesterol. The introduction of additional hydroxyl groups to the cholesterol skeleton facilitates the flux of oxysterols across the blood brain barrier, and oxysterols have been implicated in mediating a number of cholesterol-induced metabolic effects. Oxysterols are difficult to analyze by atmospheric pressure ionization mass spectrometry on account of the absence of basic or acidic functional groups in their structures. In this communication, we report a method for the derivatization and analysis of oxysterols by electrospray mass spectrometry. Oxysterols with a 3␤-hydroxy-⌬ 5 structure were converted by cholesterol oxidase to 3-oxo-⌬ 4 steroids and then derivatized with the Girard P reagent to give Girard P hydrazones, which were subsequently analyzed by tandem mass spectrometry. The improvement in sensitivity for the analysis of 25-hydroxycholesterol upon oxidation and derivatization was over 1000. (J Am Soc Mass Spectrom 2006, 17, 341-362)

show abstract

Importance of a Novel Oxidative Mechanism for Elimination of Intracellular Cholesterol in Humans

Cited by 152 publications

References 19 publications

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Elimination of Cholesterol in Macrophages and Endothelial Cells by the Sterol 27-Hydroxylase Mechanism

Analysis of oxysterols by electrospray tandem mass spectrometry

Contact Info

Product

Resources

About