Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol

The brain is the most cholesterol-rich organ in the body. Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. Very recently we showed that there is a continuous age-dependent flux of 24(S)-hydroxycholesterol from the human brain into the circulation (Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, Å., Diczfalusy, U., and Björkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799–9804). Here we measured the rate of synthesis of cholesterol as well as the conversion of cholesterol into 24(S)-hydroxycholesterol in rat brain in vivo with use of an18O2 inhalation technique and mass isotopomer distribution analysis. Cholesterol synthesis was found to correspond to 0.03 ± 0.01% of the pool per h. Conversion of cholesterol into 24(S)-hydroxycholesterol was of a similar magnitude, about 0.02% of the pool per h. Brain microsomes converted endogenous cholesterol into 24(S)-hydroxycholesterol at a similar rate when incubated in the presence of NADPH. When incubated with whole homogenate and subcellular fractions of rat brain, there was no significant conversion of tritium-labeled 24-hydroxycholesterol into more polar products. Plasma from 18O2-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of 18O similar to that in 24(S)-hydroxycholesterol in the brain.The results suggest that the present 24(S)-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats. There is a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol with a rapid turnover of the small pool of the latter oxysterol due to leakage to the circulation (half-life of brain 24(S)-hydroxycholesterol is about 0.5 days as compared with 2–4 months for brain cholesterol). It is evident that the 24(S)-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain. The brain is the most cholesterol-rich organ in the body. Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. Very recently we showed that there is a continuous age-dependent flux of 24(S)-hydroxycholesterol from the human brain into the circulation (Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, Å., Diczfalusy, U., and Björkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799–9804). Here we measured the rate of synthesis of cholesterol as well as the conversion of cholesterol into 24(S)-hydroxycholesterol in rat brain in vivo with use of an18O2 inhalation technique and mass isotopomer distribution analysis. Cholesterol synthesis was found to correspond to 0.03 ± 0.01% of the pool per h. Conversion of cholesterol into 24(S)-hydroxycholesterol was of a similar magnitude, about 0.02% of the pool per h. Brain microsomes converted endogenous cholesterol into 24(S)-hydroxycholesterol at a similar rate when incubated in the presence of NADPH. When incubated with whole homogenate and subcellular fractions of rat brain, there was no significant conversion of tritium-labeled 24-hydroxycholesterol into more polar products. Plasma from 18O2-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of 18O similar to that in 24(S)-hydroxycholesterol in the brain. The results suggest that the present 24(S)-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats. There is a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol with a rapid turnover of the small pool of the latter oxysterol due to leakage to the circulation (half-life of brain 24(S)-hydroxycholesterol is about 0.5 days as compared with 2–4 months for brain cholesterol). It is evident that the 24(S)-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain. The largest pool and concentration of cholesterol in the body is found in the brain. Being a constituent of myelin and cell membranes cholesterol is important for the function of this organ and an inborn defect in cholesterol synthesis is associated with serious neurological and mental dysfunctions (1Tint G.S. Irons M. Elias E.R. Batta A.K. Frieden R. Chen T.S. New Engl. J. Med. 1994; 330: 107-113Crossref PubMed Scopus (664) Google Scholar). Brain cholesterol is efficiently protected from exchange with circulating lipoproteins by the blood-brain barrier (2Dietschy J.M. Turley S.D. Spady D.K. J. Lipid Res. 1993; 34: 1637-1659Abstract Full Text PDF PubMed Google Scholar). In accordance with this, most recent studies have favored the view that the majority of brain cholesterol is synthesized locally although at a low rate (for a review, see Ref. 3Snipes G.J. Suter U. Bittman R. Subcellular Biochemistry. 28. Plenum Press, New York1997: 173-204Google Scholar). Using in vivo and in vitrotechniques the estimated half-life of cholesterol has been found to be 4–6 months in rats (4Serougne-Gautheron C. Chevallier F. Biochim. Biophys. Acta. 1973; 316: 244-250Crossref PubMed Scopus (18) Google Scholar, 5Andersson M. Elmberger P.G. Edlund C. Kristensson K. Dallner G. FEBS Lett. 1990; 269: 15-18Crossref PubMed Scopus (83) Google Scholar). The protection of brain cholesterol from exchange with circulating lipoprotein by the blood-brain barrier is not absolute (6Gordion E.L. Danielsson P.E. Ngvyen T.S. Winn H.R. In Vitro Cell Dev. Biol. 1991; 27A: 312-326Crossref PubMed Scopus (61) Google Scholar, 7.De Vries, H. (1995) Characteristics of Blood-Brain Barrier Endothelial Cells in Response to Inflammatory Stimuli. Thesis, Costar Europe Ltd., Badhoevededorp, The Netherlands.Google Scholar) but this exchange seems to be low in relation to the local synthesis of cholesterol. To what extent there is a flux of unmetabolized cholesterol in the opposite direction from the brain into the circulation, is not known. If the blood-brain barrier is equally effective in both directions to prevent flux of cholesterol, there is a need for another more specific mechanism for elimination of cholesterol from the brain to compensate for the synthesis under steady-state conditions. Very recently we described an age-dependent net flux of 24(S)-hydroxycholesterol from the human brain into the circulation (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and that be of for cholesterol homeostasis in the brain. The concentration of 24(S)-hydroxycholesterol was found to be in the brain in organ the with the that most circulating 24(S)-hydroxycholesterol from the brain. To the of this mechanism for elimination of cholesterol from the brain, we have an for studies synthesis of cholesterol and in use of an inhalation technique I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). technique the that synthesis of cholesterol as well as of cholesterol into of a function that into the Conversion of cholesterol into 24-hydroxycholesterol has been in in of and rat brain Biochim. Biophys. Acta. PubMed Scopus Google Scholar, A.K. J. 1973; PubMed Scopus Google Scholar). The low of conversion a of the Using microsomes from rat brain and as and a conversion of into 24-hydroxycholesterol of a Biochim. Biophys. Acta. PubMed Scopus Google Scholar). A.K. J. 1973; PubMed Scopus Google Scholar) a similar conversion of cholesterol when incubated with brain microsomes under the conditions. the of the the of of the cholesterol with the endogenous cholesterol be was not to the of the from that is to the very low cholesterol in rat brain microsomes under with use of the In the of the cholesterol in the brain be from the brain as as a To the latter we have 24-hydroxycholesterol and incubated with of rat brain under conditions. and of and in from this (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). with a specific of was from The and was by and was from in of 24-hydroxycholesterol was from cholesterol as described for of tritium-labeled PubMed Scopus Google Scholar). The was by as The was as by as and was with 24-hydroxycholesterol to have a specific of rats of an In in a rat and rats The to a and The by the at the The rats and and of the and with the in of with a in a The was by at and The the was in the In a was by of the at for and the in the of brain was as described by S. S. Batta A.K. G. J. Lipid Res. Full Text PDF PubMed Google Scholar). The as was found to ± of and ± of The contained about of and of The contained about of cholesterol in an to of the of fractions incubated in a of of the for at with of NADPH. In with was to the In specific was to the in of of of In specific of 24-hydroxycholesterol in of was incubated with brain whole homogenate under the as and with In the in a about in The contained about and in The the was with under to the of contained the The was into the and a of was by the the from the with the to the a of the and an with the was of the a and by another and for by mass I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The enrichment of 18O was found to be ± under the The inhalation as described I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) but with a the rats to be to a concentration of and was that from and The of the was to in with the of and elimination of and by the was to a and the a continuous in the The absolute concentration of in and In most of the of and of the the in the in the of the was to and as described S. U. PubMed Scopus Google Scholar). The oxysterol fractions converted into and by an mass was as with a of in in a at was The was at for at a rate of to and to The mass was in a the and for of of and In the in vivo the at was to the of of in the was in In the of 24(S)-hydroxycholesterol in the and low to for and in the at and In with 24(S)-hydroxycholesterol with an 18O at was that the was of the at the was for of the of in the in vivo in in and was the and In the of circulating a small of the of 18O of to Ref. I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In the of 24(S)-hydroxycholesterol of a subcellular a rat the from the isotopomer of 24(S)-hydroxycholesterol was from the at Ref. I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The and in the of enrichment of 18O in the the and of and the of from The the of the of the of the the the in the was found to have an of ± in the of 24(S)-hydroxycholesterol from whole brain subcellular fractions from brain and about in the of 24(S)-hydroxycholesterol from The 24(S)-hydroxycholesterol in the was from the microsomes rat to In the of the very low enrichment of 18O in cholesterol in the brain of rats to in of and by The was as with the mass the at and the at cholesterol was in In the the at and was measured is not by the in the to the of and the of was to the 18O enrichment in cholesterol with a of as well as cholesterol, was by mass with use of as described S. U. PubMed Scopus Google I. R. Acta. PubMed Scopus Google Scholar). The 24-hydroxycholesterol was to as in the was with a The of was by the rats to with for in a significant of 18O into brain cholesterol the brain have been by to extent a the be that of the small of 18O have been due to by circulating cholesterol. The latter an enrichment of In the with the rat for the enrichment was found to be in brain cholesterol and in circulating cholesterol. the concentration of cholesterol in the brain is and the concentration in the is of this in a is evident that a small with cholesterol have a significant the by a of 18O in brain cholesterol by 0.01% under specific conditions. to the very low turnover of brain cholesterol (4Serougne-Gautheron C. Chevallier F. Biochim. Biophys. Acta. 1973; 316: 244-250Crossref PubMed Scopus (18) Google Scholar, 5Andersson M. Elmberger P.G. Edlund C. Kristensson K. Dallner G. FEBS Lett. 1990; 269: 15-18Crossref PubMed Scopus (83) Google the of synthesized cholesterol be to cholesterol When into the enrichment of 18O in the inhalation and the of in the synthesis rate was to be and of the cholesterol pool per in the rats. is with a half-life of 2–4 In (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. 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It be that the rate of of 18O in 24(S)-hydroxycholesterol in the was that in the in the of synthesized 24(S)-hydroxycholesterol and the elimination of cholesterol by the 24(S)-hydroxylase mechanism be about 0.02% per in the It is of to the rate of elimination of cholesterol by the mechanism with the rate of synthesis of cholesterol in the rate was 0.02% of the pool per in the rat and of the pool per in the rat in Cholesterol was by the mechanism at a rate about more of synthesis in the rats To the flux of 24(S)-hydroxycholesterol from the brain into the circulation, from of the rats and with to enrichment of 18O in 24(S)-hydroxycholesterol and in the circulating Ref. I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). in enrichment of 18O in 24(S)-hydroxycholesterol was similar to that of 24(S)-hydroxycholesterol from the brain of the The enrichment of 18O in and in was found to and in the in the rats as In the in a rat was for and for a contained and with an 18O of and from the rat contained and with an 18O It is evident that there is a rate of elimination of synthesized and synthesized of brain microsomes with and under the described by A.K. J. 1973; PubMed Scopus Google Scholar) into with as in In the small extent of conversion of the cholesterol in of of the of and the of of the cholesterol If be to most of the endogenous cholesterol from brain microsomes with of a conversion of cholesterol be S. S. Batta A.K. G. J. Lipid Res. Full Text PDF PubMed Google Scholar) of the brain microsomes of the of cholesterol. the 24(S)-hydroxylase is to be with cholesterol, the was to the of 24(S)-hydroxycholesterol by this in brain microsomes and Using the and mass and a S. U. 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In view of a that 24(S)-hydroxycholesterol in rat brain Biochim. Biophys. Acta. PubMed Scopus Google Scholar) and that the flux of 24(S)-hydroxycholesterol from the human brain seems to be age-dependent (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google microsomes from of rats about The enrichment of 18O in 24(S)-hydroxycholesterol in this was found to be about per to a conversion of the endogenous cholesterol of about per h. from the brain of a rat about In this endogenous cholesterol was converted into 24(S)-hydroxycholesterol at a rate of about 0.01% per h. The conversion of brain cholesterol into 24(S)-hydroxycholesterol to be in rats as compared with rats. as well as and of brain incubated with tritium-labeled 24-hydroxycholesterol with under to The extent of conversion to more polar was in Brain cholesterol has been in vivo with use of cholesterol to cholesterol with use of tritium-labeled (for a review, see Ref. 3Snipes G.J. Suter U. Bittman R. Subcellular Biochemistry. 28. Plenum Press, New York1997: 173-204Google Scholar). The present in vivo technique has in relation to is by in the body and there is little no of to I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, I. A. J. Biol. Full Text PDF PubMed Google Scholar, G. I. A. J. PubMed Scopus Google of a rat to a rapid in by The to about of I. A. J. Biol. Full Text PDF PubMed Google Scholar) and is to a of a specific that be for turnover The of the technique is that is and for of the enrichment in the The technique was of the very slow conversion of endogenous brain cholesterol into The with this technique is when that the rate of 24(S)-hydroxylation of cholesterol at a rate of about 0.02% per the pool of 24(S)-hydroxycholesterol has a turnover of about per h. to a conversion of of cholesterol is very to is to the of 18O in 24(S)-hydroxycholesterol with use of cholesterol is that there is an with to the of of this cholesterol with the endogenous It be that the of cholesterol in brain is in The rate of synthesis of cholesterol in rat brain found of the pool per to a half-life of 2–4 is of the as has been use of an in of cholesterol from rat brain, the half-life was found to be about months (4Serougne-Gautheron C. Chevallier F. Biochim. Biophys. Acta. 1973; 316: 244-250Crossref PubMed Scopus (18) Google Scholar). use of technique with of rat brain, the estimated half-life of cholesterol was found to be about months M. Elmberger P.G. Edlund C. Kristensson K. Dallner G. FEBS Lett. 1990; 269: 15-18Crossref PubMed Scopus (83) Google Scholar). The turnover of brain cholesterol may as a of the and of the There was a in cholesterol synthesis in the rats the that about the and to the The most rapid synthesis was in the rat for to the this rat may have been more the rats and at present we the that this may cholesterol The pool of 24(S)-hydroxycholesterol in rat brain is about of that of cholesterol (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). It is evident from the present results that this pool has a rapid turnover as compared with brain cholesterol. The estimated half-life of 24(S)-hydroxycholesterol was found to be about as compared with about 2–4 months for cholesterol. In there may be by the brain the may into the to the may be locally to another oxysterol that may the blood-brain barrier into the may the blood-brain In the (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) we measured the concentration of 24(S)-hydroxycholesterol in human and found that of the flux of this from the brain the The that there is a local of 24-hydroxycholesterol in the brain was significant conversion of tritium-labeled 24-hydroxycholesterol into the more polar was is in with recent results by J. (1996) of and in and Thesis, Scholar). In to and 24-hydroxycholesterol was not by rat and very small of 24-hydroxycholesterol in conversion be in the present with the that unmetabolized 24(S)-hydroxycholesterol the blood-brain is with that membranes at of cholesterol F. J. Lipid Res. Full Text PDF PubMed Google Scholar). If there is a flux of unmetabolized 24(S)-hydroxycholesterol from the brain into the circulation and most of the 24(S)-hydroxycholesterol in the circulation from the brain, the 18O in this be to be about the in the circulation as in the brain in the was found to be the If most of the circulating 24(S)-hydroxycholesterol from the brain, is evident that there be a rapid the of 24-hydroxycholesterol over the blood-brain The of 18O into 24(S)-hydroxycholesterol was in the circulating and In this may be due to in rate of elimination of the oxysterol in the rate of exchange of a pool of synthesized with that in has been that most of the in the circulation is by the cholesterol and that there is a rapid turnover of this I. S. K. J. Lipid Res. Full Text PDF PubMed Google Scholar). has been that most of the present in the circulation is and that there is a rapid flux of this to the I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. G. U. K. J. I. Biol. PubMed Scopus Google Scholar). The most for the low in the circulating 24(S)-hydroxycholesterol is that the rate of synthesis of this oxysterol in relation to pool is for the of the for the low of 18O in circulating 24(S)-hydroxycholesterol be a slow rate of turnover in this to with 24-hydroxycholesterol in the half-life of this is very h. and I. Björkhem, seems that a half-life in the circulation the low of 18O in circulating and have a half-life in the circulation of rats is evident from the in to concentration of 24(S)-hydroxycholesterol (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and of the 24(S)-hydroxycholesterol in the circulation be from the The small in relation to the brain, and was that the of rats of the of 24(S)-hydroxycholesterol present in the brain. In of was that the of 18O in 24(S)-hydroxycholesterol present in the was similar to that in 24(S)-hydroxycholesterol from the brain of the The very small of a more the turnover of 24(S)-hydroxycholesterol in the The present results Biochim. Biophys. Acta. PubMed Scopus Google A.K. J. 1973; PubMed Scopus Google Scholar) that brain microsomes 24(S)-hydroxylase cholesterol. and was for the seems that a of is has been that brain of of and of H. I. Google Scholar, J. J. Scholar, Brain Res. 1993; PubMed Scopus Google as well as Brain Res. 1993; PubMed Scopus Google Scholar, I. PubMed Scopus Google Scholar). G. M. M. R. J. Biol. Full Text Full Text PDF Scopus Google Scholar) described a that is in the brain. When in this was found to and G. K. R. M. I. J. R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and no significant cholesterol. The of for 24(S)-hydroxylation of cholesterol has not been the specific in the rate of 24(S)-hydroxylation of endogenous cholesterol in brain microsomes was found to be similar to the rate of 24(S)-hydroxylation of cholesterol in the in vivo 0.02% conversion per The a more of the of the The age-dependent in of circulating 24(S)-hydroxycholesterol (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) to cholesterol in brain microsomes from very and rats. the to be in from the was low to this is the in of 24(S)-hydroxycholesterol in the circulation of and (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In view of the low exchange with lipoproteins in the circulation G.J. Suter U. Bittman R. Subcellular Biochemistry. 28. Plenum Press, New York1997: 173-204Google is evident that the local synthesis of cholesterol in the brain be by an elimination that is similar to this In a in the brain is the rate of synthesis be the rate of The present that the rate of of cholesterol as 24(S)-hydroxycholesterol from the brain of rats is at of the rate of cholesterol synthesis is with the 24(S)-hydroxylase mechanism as the most important for elimination of cholesterol from this elimination of unmetabolized cholesterol is to be has been a in and homeostasis of cholesterol in the brain G.J. Suter U. Bittman R. Subcellular Biochemistry. 28. Plenum Press, New York1997: 173-204Google Scholar, Biochim. Biophys. Acta. PubMed Scopus Google Scholar). to and and there is a flux of lipoproteins into the It has been Biochim. Biophys. Acta. PubMed Scopus Google Scholar) that a of cholesterol for the of of cholesterol per from the human brain. the of 24(S)-hydroxycholesterol in the and in a we have found (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) that the rate of elimination of cholesterol from the human brain by the present mechanism is about 4–6 per The rate of synthesis of cholesterol in the human brain is not and we not the relation this synthesis and the for of cholesterol in and a and is that cholesterol be from to extent by a mechanism conversion of cholesterol into the more polar and J. A. G. U. K. J. I. Biol. PubMed Scopus Google Scholar, I. U. C. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). the brain a H. I. Google Scholar) and the be that cholesterol may be from the brain by this The of the in the brain that of the 24(S)-hydroxylase and this was found to be low to be measured by the present The concentration of in the brain is that of and we have to a net flux of from the brain into the circulation (8Lütjohann G. I. U. I. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of a in the brain has been Brain Res. 1993; PubMed Scopus Google Scholar, I. PubMed Scopus Google Scholar). from the in I. PubMed Scopus Google this of cholesterol 24(S)-hydroxylase and is not to be of for the turnover of cholesterol in the brain. in to the low in the brain by the present technique has Björkhem, Breuer, A. and In to a for cholesterol over the blood-brain 24(S)-hydroxycholesterol is a of cholesterol synthesis A.K. D.K. J. Biol. Full Text PDF PubMed Google Scholar). In both of cholesterol and of cholesterol synthesis in the brain may be under of the synthesis of cholesterol in the body is in in and the of a from a to there is a in the rate of synthesis of cholesterol (2Dietschy J.M. Turley S.D. Spady D.K. J. Lipid Res. 1993; 34: 1637-1659Abstract Full Text PDF PubMed Google Scholar). found a cholesterol 24(S)-hydroxylase in brain microsomes from rats as compared with rats. is with a that the of 24(S)-hydroxycholesterol in the brain in rats in rats Biochim. Biophys. Acta. PubMed Scopus Google Scholar). the of 24(S)-hydroxycholesterol in the brain of rats of for cholesterol synthesis is not known. the present of we that the elimination of brain cholesterol is to cholesterol synthesis and that the age-dependent in circulating of this oxysterol to in cholesterol The of a of the cholesterol 24(S)-hydroxylase for cholesterol homeostasis in the brain be when the of for the hydroxylation has been and characterized at a The of and is