Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr−/−, apoA-I−/−) mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5- to 2-fold lower plasma cholesterol concentration compared with diet-fed LDLr−/− mice. The accumulation of cholesterol predominantly in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing deficits in genes regulating cellular cholesterol homeostasis. Exploring the relationship between cholesterol balance and inflammation, we have examined the time course of cholesterol accumulation in a number of extrahepatic tissues and correlated with the onset of inflammation in diet-fed LDLr−/−, apoA-I−/− mice. After 4 weeks of diet, LDLr−/−, apoA-I−/− mice showed a significant increase in skin cholesterol mass compared with LDLr−/− mice. In addition, after 4 weeks on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by increases in tumor necrosis factor-α, cyclooxygenase-2, and langerin mRNA, which were not seen in the liver. Overall, these data suggest that as early as 4 weeks after starting the diet, the accumulation of skin cholesterol and the onset of inflammation occur concurrently. In summary, the use of hypercholesterolemic LDLr−/−, apoA-I−/− mice may provide a useful tool to investigate the role that apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation. Diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr−/−, apoA-I−/−) mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5- to 2-fold lower plasma cholesterol concentration compared with diet-fed LDLr−/− mice. The accumulation of cholesterol predominantly in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing deficits in genes regulating cellular cholesterol homeostasis. Exploring the relationship between cholesterol balance and inflammation, we have examined the time course of cholesterol accumulation in a number of extrahepatic tissues and correlated with the onset of inflammation in diet-fed LDLr−/−, apoA-I−/− mice. After 4 weeks of diet, LDLr−/−, apoA-I−/− mice showed a significant increase in skin cholesterol mass compared with LDLr−/− mice. In addition, after 4 weeks on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by increases in tumor necrosis factor-α, cyclooxygenase-2, and langerin mRNA, which were not seen in the liver. Overall, these data suggest that as early as 4 weeks after starting the diet, the accumulation of skin cholesterol and the onset of inflammation occur concurrently. In summary, the use of hypercholesterolemic LDLr−/−, apoA-I−/− mice may provide a useful tool to investigate the role that apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation. The plasma HDL apolipoprotein A-I (apoA-I) concentration is a powerful inverse correlate of atherosclerosis risk in humans (1Sprecher H. Metabolism of highly unsaturated n-3 and n-6 fatty acids..Biochim. Biophys. Acta. 2000; 1486: 219-231Crossref PubMed Scopus (662) Google Scholar). The most prominent mechanism explaining its atheroprotective role is through the directional movement of peripheral tissue cholesterol to the liver via a pathway referred to as “reverse cholesterol transport.” This pathway describes a mechanism of cholesterol removal and was first proposed by Glomset and Norum (2Cho H.P. Nakamura M. Clarke S.D. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase..J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar). Excess cholesterol is removed from peripheral tissues and cells organized by apoA-I into phospholipid complexes, then transported to the liver for excretion. A number of steps have been shown to be critical in completing the overall pathway (3Cho H.P. Nakamura M.T. Clarke S.D. Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase..J. Biol. Chem. 1999; 274: 471-477Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar). In vivo studies aimed at establishing the role of HDL apoA-I as the main physiological efflux acceptor of peripheral tissue cholesterol have shown that the absence of apoA-I has little or no effect on centripetal cholesterol transport, suggesting that the movement of peripheral tissue cholesterol via HDL apoA-I is not a rate-limiting step in net cholesterol removal (4Wang Y. Botolin D. Christian B. Busik J. Xu J. Jump D.B. Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases..J. Lipid Res. 2005; 46: 706-715Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 5Zheng X. Tocher D.R. Dickson C.A. Bell J.G. Teale A.J. Highly unsaturated fatty acid synthesis in vertebrates: new insights with the cloning and characterization of a delta6 desaturase of Atlantic salmon..Lipids. 2005; 40: 13-24Crossref PubMed Scopus (177) Google Scholar, 6Scott B.L. Bazan N.G. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver..Proc. Natl. Acad. Sci. USA. 1989; 86: 2903-2907Crossref PubMed Scopus (383) Google Scholar, 7Igarashi M. Ma K. Chang L. Bell J.M. liver of to acid in on a Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In other the role of apoA-I in cholesterol has been with on macrophage cholesterol and not peripheral tissue cholesterol In Ma K. Chang L. Bell J.M. of acid is a of the in brain of Biophys. Acta. PubMed Scopus Google apoA-I was found to in knockout mice after to In mice in and apoA-I were found to have to lower plasma cholesterol mice in and macrophage In of the lower plasma the apoA-I and double knockout mice in the knockout mice macrophage M. Ma K. Chang L. Bell J.M. acid is to acid in brain and liver of a 2005; Scholar). a of the in vivo of macrophage a showed that of apoA-I cholesterol from to in mice with of plasma apoA-I Ma K. Chang L. Bell J.M. acid not to acid brain of a in 2005; PubMed Scopus Google Scholar). the was also shown to be for cholesterol M.T. fatty acid synthesis and its regulation in Full Text Full Text PDF PubMed Scopus Google Scholar). these studies suggest that macrophage cholesterol efflux little to the plasma concentration of macrophage cholesterol efflux to apoA-I is highly in and in the and of cholesterol from the S.D. M. acid synthesis from n-3 fatty in rat brain Lipid Res. Full Text Full Text PDF PubMed Google Scholar, J.M. and tissue in in n-3 fatty by of 1989; PubMed Scopus Google Scholar). In to role in cholesterol and its as of cellular inflammation. A of that the and of atherosclerosis J.M. M. M. The of acid on the of of to and of in 1989; PubMed Scopus Google Scholar, Ma K. Bell J.M. M. D. of n-3 fatty acid increases and in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, Ma K. Bell J.M. of acid in rat brain by weeks of nutritional of n-3 fatty PubMed Scopus Google as as the onset of inflammation by the of the of into The role in cholesterol removal and its role as have not been the studies in diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr−/−, apoA-I−/−) double knockout in which and tissue cholesterol balance was as a of time and its relationship to inflammation was also In to the role of apoA-I in the of we the diet-fed LDLr−/−, apoA-I−/− mouse studies from for of the of on the of the PubMed Scopus Google and by J. and of the for on and in and PubMed Scopus Google Scholar, K. acid and of in the PubMed Scopus Google have shown that and mouse models useful for the between cholesterol homeostasis and inflammation. 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A concentration was by a from plasma was by a from tissue cholesterol of the were and in as M. Ma K. Chang L. Bell J.M. liver of to acid in on a Lipid Res. Full Text Full Text PDF PubMed Scopus Google and the was also B.L. Bazan N.G. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver..Proc. Natl. Acad. Sci. USA. 1989; 86: 2903-2907Crossref PubMed Scopus (383) Google after which tissue cholesterol was by for of the of on the of the PubMed Scopus Google Scholar). cholesterol in the was removed the in M. of by Biophys. Acta. PubMed Scopus Google Scholar). significant in between the diet-fed was in of the weeks of the diet-fed LDLr−/−, apoA-I−/− mice showed a increase in compared with diet-fed LDLr−/− mice. 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M. the of by the liver in Biol. 2005; PubMed Scopus Google Scholar). the in the skin of diet-fed LDLr−/−, apoA-I−/− and LDLr−/− mass were on skin skin of diet-fed LDLr−/− cholesterol and for of the In from diet-fed LDLr−/−, apoA-I−/− of the was in the of data suggest that the accumulation of skin cholesterol was via and from the cholesterol in the The inflammation associated with the accumulation of cholesterol in the skin of diet-fed LDLr−/−, apoA-I−/− mice was also by increase in plasma A a of inflammation A were at and weeks shown for weeks after the at and weeks were the plasma A between diet-fed LDLr−/−, apoA-I−/− and LDLr−/− mice. suggest that the accumulation of skin cholesterol and the associated and were for a in these mice. 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A for in vivo into and brain and critical Res. Res. PubMed Scopus Google Scholar, In vivo fatty acid into brain in to plasma and PubMed Scopus Google and and LDLr−/− double knockout mouse models In vivo and for and brain Lipid 2005; PubMed Scopus Google Scholar, Chang of acid not and of acid and in rat 2000; PubMed Scopus Google Scholar). to from diet-fed LDLr−/− and J. M. of acid in the rat and Lipid Res. Full Text Full Text PDF PubMed Google Scholar, J. J. of on and liver fatty in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, not acid and acid PubMed Scopus Google double knockout mice have shown cholesterol accumulation in the despite a plasma cholesterol In these the skin was the of cholesterol the and were also found to be by data were on in liver cholesterol in diet-fed LDLr−/− and mice J. J. of on and liver fatty in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). that of these mouse models which also to to the accumulation of cholesterol in the is that of deficits in genes regulating cholesterol homeostasis and be to that diet-fed LDLr−/−, apoA-I−/− mice plasma HDL a accumulation of skin cholesterol a in the cholesterol that the to increase in in LDLr−/−, apoA-I LDLr−/− mice for of the of on the of the PubMed Scopus Google Scholar, H. in synthesis of and by and Res. PubMed Scopus Google to by skin and in the accumulation of cholesterol in the of suggest that the mechanism of cholesterol accumulation in the skin may be The first and most to with a cholesterol is that the skin to accumulate of cholesterol in to the in LDLr−/−, apoA-I−/− other tissues in the In addition, the role of in not to be a number of of skin cholesterol in the absence of M. D. H. M. in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. B. H. M. the of by the liver in Biol. 2005; PubMed Scopus Google Scholar, J. A for in vivo into and brain and critical Res. Res. PubMed Scopus Google Scholar, In vivo fatty acid into brain in to plasma and PubMed Scopus Google Scholar, In vivo and for and brain Lipid 2005; PubMed Scopus Google Scholar, Chang of acid not and of acid and in rat 2000; PubMed Scopus Google Scholar, J. M. of acid in the rat and Lipid Res. Full Text Full Text PDF PubMed Google Scholar). for the accumulation of skin cholesterol may be to of in and LDLr−/− mice D. Y. Christian B. Jump D.B. acid rat by and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. synthesis and of brain in the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). cells cells that in the to and peripheral of fatty by the developing rat PubMed Scopus Google Scholar). cells the of and the of which the and J. M. low density lipoprotein is in early Y. Acad. Sci. 1999; PubMed Scopus Google Scholar). The balance in and is critical in maintaining B. of through the pathway of is in apolipoprotein 40: Full Text Full Text PDF PubMed Scopus Google Scholar). the skin is a for was in or knockout mice on for weeks D. Y. Christian B. Jump D.B. acid rat by and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. synthesis and of brain in the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). in these mass accumulation of cholesterol in the skin was not in diet-fed LDLr−/− was that also were in skin by weeks and were shown to in the in to inflammation, and was by the of HDL or The between skin and cholesterol homeostasis to be The accumulation of skin cholesterol seen in studies diet-fed LDLr−/−, apoA-I−/− mice as as in other hypercholesterolemic mouse models may or of the in and diet-fed and knockout as not acid and acid PubMed Scopus Google Scholar, H. in synthesis of and by and Res. PubMed Scopus Google Scholar). In of we langerin in 4 weeks after the diet, in time to mass of cholesterol in the langerin were in LDLr−/−, apoA-I−/− compared with LDLr−/− mice. skin and were in LDLr−/−, apoA-I−/− mice at 4 suggest that the of cholesterol and is the for a between cholesterol homeostasis and is with is the significant increase in skin tumor necrosis factor-α, and in LDLr−/−, apoA-I−/− mice as early as 4 weeks after starting the these of inflammation correlate with the increase in phospholipid and in the skin of LDLr−/−, apoA-I−/− mice. In studies of not acid and acid PubMed Scopus Google Scholar, H. in synthesis of and by and Res. PubMed Scopus Google is that was HDL or was into the knockout suggesting that the accumulation of phospholipid or its to the in the In to the between cholesterol inflammation, and is also growing in the between and skin inflammation D. for of acid from plasma into brain of Lipid Res. Full Text PDF PubMed Google Scholar). In the diet-fed LDLr−/−, apoA-I−/− mice showed starting as early as weeks after starting the diet, with increase in skin In has been to the of in the which is to be in by the of and in the Chang and of in mammalian Lipid Res. Full Text Full Text PDF PubMed Google Scholar, acid of tissue in for the Lipid Res. PubMed Scopus Google Scholar). The of skin has also been to the of human D. H. of lipoprotein on and of low density lipoprotein and in a in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google which in the and regulation of the these suggest that cellular cholesterol balance is and skin In summary, we that in hypercholesterolemic LDLr−/−, apoA-I−/− mice a of the between cellular cholesterol inflammation, and The and for on cholesterol on and mouse The also and and and for their The for of cholesterol studies were by from the and of and to