Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein

Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1−/−) mice that lack HDL and wild-type (WT) mice were intravenously injected with chylomicron-like emulsion particles that contained radiolabeled cholesterol that is liberated in the liver and partly reenters the circulation. Both groups secreted radiolabeled cholesterol from plasma into intestinal lumen and TICE was unaltered between the two mouse models. To further investigate the role of HDL, we injected HDL with radiolabeled cholesterol in WT mice and Abca1−/−×Sr-b1−/− mice that lack HDL and are also unable to clear HDL via the liver. The intestines of both mice were unable to take up and secrete radiolabeled cholesterol from HDL via TICE. Although a generally accepted major player in the hepatobiliary route-based cholesterol excretion, HDL plays no significant role in TICE in mice. Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1−/−) mice that lack HDL and wild-type (WT) mice were intravenously injected with chylomicron-like emulsion particles that contained radiolabeled cholesterol that is liberated in the liver and partly reenters the circulation. Both groups secreted radiolabeled cholesterol from plasma into intestinal lumen and TICE was unaltered between the two mouse models. To further investigate the role of HDL, we injected HDL with radiolabeled cholesterol in WT mice and Abca1−/−×Sr-b1−/− mice that lack HDL and are also unable to clear HDL via the liver. The intestines of both mice were unable to take up and secrete radiolabeled cholesterol from HDL via TICE. Although a generally accepted major player in the hepatobiliary route-based cholesterol excretion, HDL plays no significant role in TICE in mice. Elevated circulating cholesterol levels are an important risk factor for atherosclerosis that is characterized by the accumulation of LDL-cholesterol in macrophages of the arterial wall (1Ross R. Atherosclerosis–an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19200) Google Scholar). Statin treatment reduces LDL-cholesterol levels and is currently the most potent cholesterol-lowering therapy available (2Baigent C. Keech A. Kearney P.M. Blackwell L. Buck G. Pollicino C. Kirby A. Sourjina T. Peto R. Collins R. et al.Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (5749) Google Scholar). In the search for new therapeutic approaches, the reverse cholesterol transport (RCT) pathway has gained much attention during the last decade (3Tall A.R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.J. Intern. Med. 2008; 263: 256-273Crossref PubMed Scopus (338) Google Scholar, 4Rader D.J. Mechanisms of disease: HDL metabolism as a target for novel therapies.Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: 102-109Crossref PubMed Scopus (54) Google Scholar). RCT via the commonly known hepatobiliary route describes the transport of peripheral cholesterol back to the liver for biliary secretion. In this pathway, HDL and apoAI, the major apolipoprotein of HDL, play a profound role. ApoAI and HDL take up cellular cholesterol from peripheral tissues, including macrophages in the arterial wall, via the cholesterol transporters ABC A1 and G1, respectively (3Tall A.R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.J. Intern. Med. 2008; 263: 256-273Crossref PubMed Scopus (338) Google Scholar). In a scavenger receptor class BI (SR-BI)-dependent manner, HDL-cholesterol is delivered to the liver from where cholesterol can reenter the circulation via VLDL production or can be excreted via bile. Recently, we reported on an additional nonhepatobiliary-related route for RCT, the trans-intestinal cholesterol efflux (TICE) pathway (5van der Velde A.E. Vrins C.L. Van den Oever K. Kunne C. Oude Elferink R.P. Kuipers F. Groen A.K. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice.Gastroenterology. 2007; 133: 967-975Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). This pathway describes the transport of cholesterol from blood to the intestinal lumen directly via enterocytes. TICE, which is predominantly exerted at the proximal part of small intestine, can contribute up to 70% of the daily total body neutral sterol secretion in mice. The activity of this pathway has been confirmed by Temel et al. (6Temel R.E. Sawyer J.K. Yu L. Lord C. Degirolamo C. McDaniel A. Marshall S. Wang N. Shah R. Rudel L.L. et al.Biliary sterol secretion is not required for macrophage reverse cholesterol transport.Cell Metab. 2010; 12: 96-102Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar) who demonstrated in elegant studies that acute biliary diversion does not influence intestinal cholesterol excretion significantly. An important issue that remains to be resolved for TICE is the identification of the donor particle that delivers the circulating cholesterol to the enterocyte. The intestine assembles lipids absorbed from the gut into chylomicrons and secretes these lipoprotein particles into lymph for distribution over the body (7Hussain M.M. A proposed model for the assembly of chylomicrons.Atherosclerosis. 2000; 148: 1-15Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). In addition, the intestine is an important contributor to circulating HDL levels (8Brunham L.R. Kruit J.K. Iqbal J. Fievet C. Timmins J.M. Pape T.D. Coburn B.A. Bissada N. Staels B. Groen A.K. et al.Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.J. Clin. Invest. 2006; 116: 1052-1062Crossref PubMed Scopus (419) Google Scholar). However, little is known about uptake of circulating lipoproteins by the intestine from the basolateral side. Interestingly, the rate of TICE was two-fold higher in SR-BI-deficient mice with increased HDL levels as related to an impaired delivery of HDL-cholesterol to the liver (9van der Velde A.E. Vrins C.L. Van den Oever K. Seemann I. Oude Elferink R.P. Van Eck M. Kuipers F. Groen A.K. Regulation of direct transintestinal cholesterol excretion in mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G203-G208Crossref PubMed Scopus (92) Google Scholar). It is thus conceivable that HDL is utilized for RCT via the hepatobiliary route as well as TICE. In this study, we investigated basolateral uptake of cholesterol by the intestine and the potential role for HDL in TICE. We evaluated plasma kinetics, liver uptake, and biliary and intestinal secretion of radiolabeled cholesterol, which was injected via chylomicron-like particles in mice with normal and disturbed HDL metabolism. Results reported herein indicate that TICE is not mediated significantly via HDL particles. Male wild-type (WT) mice (C57Bl/6Jico; Charles River, L'Arbresle Cedex, France) as well as the Abca1−/− (10Hamon Y. Broccardo C. Chambenoit O. Luciani M.F. Toti F. Chaslin S. Freyssinet J.M. Devaux P.F. McNeish J. Marguet D. et al.ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.Nat. Cell Biol. 2000; 2: 399-406Crossref PubMed Scopus (464) Google Scholar), Sr-bI−/− (11Rigotti A. Trigatti B.L. Penman M. Rayburn H. Herz J. Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 12610-12615Crossref PubMed Scopus (756) Google Scholar), and Abca1−/−×Sr-bI−/− mice (12Zhao Y. Pennings M. Vrins C.L. Calpe-Berdiel L. Hoekstra M. Kruijt J.K. Ottenhoff R. Hildebrand R.B. van der Sluis R. Jessup W. et al.Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI.Atherosclerosis. 2011; 218: 314-322Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar), together with their WT littermates, received standard mouse chow diet [CRE(E), no cholesterol and were The mice were on a were to the of the and by the for emulsion particles were as van Kruijt J.K. Van liver of by new therapeutic to Med. PubMed Scopus Google Scholar). a of of total was in of density The of and cholesterol from The and at a of In addition, The was to the The was a at at a of particles with an of were by HDL was from blood of by as by et al. D.J. and metabolism of in the of density lipoprotein mice and mice. for metabolism via an Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) and with HDL was with via from donor particles as reported K. H. Van W. uptake in and in of from lipoprotein by liver J. PubMed Scopus Google Scholar). particles were by of with of the at at a of in a particles with a density of were density HDL was radiolabeled by with donor particles of HDL in the of as a of protein for at in a was to and HDL was by density were by of a of and body was by chylomicron-like particles and or HDL were by were at the was via for and the proximal small intestines were with a that was of and and at a rate of as (5van der Velde A.E. Vrins C.L. Van den Oever K. Kunne C. Oude Elferink R.P. Kuipers F. Groen A.K. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice.Gastroenterology. 2007; 133: 967-975Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). This of and was to of cholesterol secretion (5van der Velde A.E. Vrins C.L. Van den Oever K. Kunne C. Oude Elferink R.P. Kuipers F. Groen A.K. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice.Gastroenterology. 2007; 133: 967-975Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). At the of the of blood was by Liver was in The total of in the plasma was on the total plasma of body J. A. S. of is but is in mice lacking the density lipoprotein Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, N. Van Van the of apolipoprotein for the receptor receptor in vivo.J. 1997; Full Text PDF PubMed Google Scholar). To liver uptake, the were and were in To intestinal uptake, the intestinal were the was in and lipids were to and A of total and J. Physiol. PubMed Scopus Google Scholar). was a To the distribution of over cholesterol and in of and plasma lipids were to and A of total and J. Physiol. PubMed Scopus Google Scholar). of in cholesterol and were by the on the were by and the distribution of was a and cholesterol were by a as H. of total cholesterol in PubMed Scopus Google Scholar). cholesterol in plasma was cholesterol from are as for TICE, as in the were by the of mice that the The for the for the of the were by the data of the last between groups were by of were to be In to the cholesterol donor for TICE, we investigated the of and contained in chylomicron-like emulsion particles to WT mice by Both and were from the circulation In we in and the of the injected is up by the liver and that no direct uptake is by the intestine van Kruijt J.K. Van liver of by new therapeutic to Med. PubMed Scopus Google Scholar). of the injected was in the which was to and D.J. and metabolism of in the of density lipoprotein mice and mice. for metabolism via an Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, der van Vrins C.L. Van H. R. K. Groen A.K. Kuipers F. of the liver receptor trans-intestinal excretion of plasma Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, this was for both that no of cholesterol from the emulsion particles to their in plasma uptake by the liver. To the distribution of both the and the between its and in the was on lipids of liver Although the in the the of was and also as In plasma of these up about of the total circulating of plasma that the activity in the circulation of the injected was over and cholesterol A distribution was for plasma activity of injected data the of the radiolabeled cholesterol uptake by the liver as demonstrated of in the Full Text PDF PubMed Google Scholar, Rudel L.L. metabolism of lipoprotein in of Full Text PDF PubMed Google M. van der Fievet C. G. Hoekstra M. Staels B. Cholesterol in mice on an ABCA1 and Biol. 2006; PubMed Scopus Google Scholar). In addition, lipoprotein of these plasma by protein demonstrated the total plasma cholesterol, both were with the HDL To TICE and biliary cholesterol we intestine and at for a of that secretion of cholesterol via TICE was higher the biliary cholesterol secretion. This confirmed that TICE plays a role in fecal neutral sterol excretion in mice (5van der Velde A.E. Vrins C.L. Van den Oever K. Kunne C. Oude Elferink R.P. Kuipers F. Groen A.K. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice.Gastroenterology. 2007; 133: 967-975Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, der van Vrins C.L. Van H. R. K. Groen A.K. Kuipers F. of the liver receptor trans-intestinal excretion of plasma Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). A of the intravenously injected radiolabeled cholesterol up by the liver is via biliary cholesterol secretion. In addition, we also with intestine that radiolabeled cholesterol is secreted into the intestinal lumen In the activity between and not Although these data direct secretion of cholesterol from blood into the intestinal lumen via TICE, not between potential cholesterol and direct uptake of radiolabeled emulsion particles by the intestine der van Vrins C.L. Van H. R. K. Groen A.K. Kuipers F. of the liver receptor trans-intestinal excretion of plasma Biol. Full Text Full Text PDF PubMed Scopus Google of radiolabeled cholesterol from chylomicron-like emulsion particles into intestine via TICE hepatobiliary body activity in a new In a we that Abca1−/− mice with no HDL levels unaltered fecal neutral sterol excretion with their WT A.K. Ottenhoff R. G. Kuipers F. cholesterol transport is not impaired in mice lacking Clin. Invest. PubMed Scopus Google Scholar). To investigate TICE is also unaltered in the of HDL, we investigated the transport of radiolabeled cholesterol from chylomicron-like emulsion particles into the intestinal To this we injected particles into Abca1−/− mice and their WT of from plasma and uptake of in Abca1−/− mice was to that in WT Interestingly, the of HDL, activity of biliary cholesterol secretion was not significantly in with the unaltered biliary cholesterol secretion reported by A.K. Ottenhoff R. G. Kuipers F. cholesterol transport is not impaired in mice lacking Clin. Invest. PubMed Scopus Google cholesterol secretion and TICE of radiolabeled cholesterol from chylomicron-like emulsion particles in Abca1−/− and mice. of emulsion particles and intestine were Cholesterol and were in the and for cholesterol are as are a significant between mouse model and WT on the Abca1−/− mice that TICE was not significantly by the of cholesterol in the the rate of TICE in mice lacking HDL was body with body in their WT the of HDL in Abca1−/− transintestinal secretion of radiolabeled cholesterol via chylomicron-like emulsion particles was with WT with a gene HDL and increased TICE (9van der Velde A.E. Vrins C.L. Van den Oever K. Seemann I. Oude Elferink R.P. Van Eck M. Kuipers F. Groen A.K. Regulation of direct transintestinal cholesterol excretion in mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G203-G208Crossref PubMed Scopus (92) Google Scholar). To investigate the increased TICE is by increased of from chylomicron-like emulsion particles to the intestinal mice and their wild-type were injected with particles. in the was from the circulation and was no between WT and mice. Interestingly, activity of cholesterol was unaltered both in and intestinal from mice The with Abca1−/− and mice are not with to the role of HDL as a cholesterol donor for TICE. We the role of HDL directly in and mice that lack HDL and are also in HDL-cholesterol via the liver (12Zhao Y. Pennings M. Vrins C.L. Calpe-Berdiel L. Hoekstra M. Kruijt J.K. Ottenhoff R. Hildebrand R.B. van der Sluis R. Jessup W. et al.Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI.Atherosclerosis. 2011; 218: 314-322Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). To or not HDL can as a cholesterol donor for TICE, we into the of HDL from the circulation was in Abca1−/−×Sr-b1−/− mice In addition, the uptake of is by the activity of cholesterol secreted into However, biliary cholesterol secretion was unaltered in the Abca1−/−×Sr-b1−/− mice (12Zhao Y. Pennings M. Vrins C.L. Calpe-Berdiel L. Hoekstra M. Kruijt J.K. Ottenhoff R. Hildebrand R.B. van der Sluis R. Jessup W. et al.Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI.Atherosclerosis. 2011; 218: 314-322Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). mice were characterized by an cholesterol secretion by the intestine (9van der Velde A.E. Vrins C.L. Van den Oever K. Seemann I. Oude Elferink R.P. Van Eck M. Kuipers F. Groen A.K. Regulation of direct transintestinal cholesterol excretion in mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G203-G208Crossref PubMed Scopus (92) Google Scholar), the rate of TICE body in the mice was with their WT Interestingly, cholesterol was secreted by the intestine in both Abca1−/−×Sr-b1−/− and WT that HDL is not up by the intestine radiolabeled cholesterol in the injected HDL be secreted via TICE The of TICE has been demonstrated in studies in mouse (5van der Velde A.E. Vrins C.L. Van den Oever K. Kunne C. Oude Elferink R.P. Kuipers F. Groen A.K. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice.Gastroenterology. 2007; 133: 967-975Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, J.M. Sawyer J.K. K. Shah R. et of cholesterol reveals a route for fecal neutral sterol Biol. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) and indicate that this pathway is also of cholesterol from a intestinal studies in Clin. Invest. PubMed Scopus Google Scholar). The of direct cholesterol secretion via the intestine to fecal sterol excretion is a novel that can the of cholesterol-lowering However, the of TICE remains to be An important that to be is which donor particle delivers the cholesterol for secretion via TICE. In the RCT pathway via the hepatobiliary HDL plays an important role D.J. J. The role of reverse cholesterol transport in and and to Full Text Full Text PDF PubMed Scopus Google Scholar). In this we important that HDL does not contribute significantly to TICE. from intestine that of chylomicron-like emulsion as a model of circulating lipoproteins N. Van Van the of apolipoprotein for the receptor receptor in vivo.J. 1997; Full Text PDF PubMed Google Scholar), the radiolabeled cholesterol can be secreted directly into the intestinal lumen of the biliary It was that these chylomicron-like emulsion particles lipoproteins in the circulation and are up by the liver van Kruijt J.K. Van liver of by new therapeutic to Med. PubMed Scopus Google Scholar, der van Vrins C.L. Van H. R. K. Groen A.K. Kuipers F. of the liver receptor trans-intestinal excretion of plasma Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) via the of and J.M. of a novel route for the of from lipoproteins to studies the 1999; PubMed Scopus Google Scholar), that part of the in the cholesterol is secreted into and part of is into the circulation and is over the lipoproteins including HDL, to the lipoprotein cholesterol of the A from et al. M. van der Fievet C. G. Hoekstra M. Staels B. Cholesterol in mice on an ABCA1 and Biol. 2006; PubMed Scopus Google Scholar) demonstrated this of cholesterol from chylomicron-like particles uptake by the liver and direct of radiolabeled cholesterol to HDL in HDL plays an important role in RCT via the hepatobiliary route and the of circulating lipoprotein cholesterol in we HDL a to directly the intestine with cholesterol for TICE. with this in mice that are characterized by HDL-cholesterol we a two-fold increase in TICE (9van der Velde A.E. Vrins C.L. Van den Oever K. Seemann I. Oude Elferink R.P. Van Eck M. Kuipers F. Groen A.K. Regulation of direct transintestinal cholesterol excretion in mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G203-G208Crossref PubMed Scopus (92) Google as demonstrated in the activity in the was which be to the increased of cholesterol in the plasma (11Rigotti A. Trigatti B.L. Penman M. Rayburn H. Herz J. Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 12610-12615Crossref PubMed Scopus (756) Google Scholar). We also that in Abca1−/− mice TICE is not with their WT In we a significant secretion of radiolabeled cholesterol from injected chylomicron-like emulsion particles via TICE. The activity of the cholesterol secreted via TICE in Abca1−/− mice was of that in their WT It be that the lack of TICE in Abca1−/− mice is to mechanisms peripheral cholesterol efflux in an HDL In addition, cholesterol be for by increased cholesterol in the HDL as a cholesterol donor for TICE was further we HDL into mice. of HDL via the liver was impaired in Abca1−/−×Sr-b1−/− mice to (11Rigotti A. Trigatti B.L. Penman M. Rayburn H. Herz J. Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 12610-12615Crossref PubMed Scopus (756) Google Scholar). no uptake of HDL by the intestine was and radiolabeled cholesterol be in the intestinal Interestingly, no uptake and secretion of cholesterol be in the WT data not that TICE is not mediated via HDL, but also that little or no uptake of HDL by the intestine studies by et al. F. I. C. M. J. G. D.J. Both the receptor and reverse cholesterol transport in mice by intestinal of Sci. 2: PubMed Scopus Google Scholar). HDL at a is not involved in TICE, is to we a two-fold increase of TICE in mice in an (9van der Velde A.E. Vrins C.L. Van den Oever K. Seemann I. Oude Elferink R.P. Van Eck M. Kuipers F. Groen A.K. Regulation of direct transintestinal cholesterol excretion in mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G203-G208Crossref PubMed Scopus (92) Google Scholar). A at the lipoprotein of these mice not an increase of the but also a of HDL lipoprotein particles and an with the Eck M. Hoekstra M. R. Kruijt J.K. Hildebrand R.B. Van receptor BI the metabolism of VLDL lipoproteins in vivo.J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the HDL particles that in mice are in (11Rigotti A. Trigatti B.L. Penman M. Rayburn H. Herz J. Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 12610-12615Crossref PubMed Scopus (756) Google Scholar). It is thus that the of HDL with the increase in TICE and indicate that TICE from lipoprotein to the metabolism of VLDL and we not been to these particles as for TICE. In an to between the of and cholesterol, we both and into chylomicron-like emulsion particles. by the was into cholesterol and together with the in the of this radiolabeled cholesterol is into the circulation and the lipoproteins that in WT mice. the from to secretion into the intestinal the between the two However, both redistribution by the liver were over and cholesterol, was not to a by the intestine for of the cholesterol on and increased HDL levels are to be partly to an RCT via the hepatobiliary route of HDL-cholesterol to atherosclerosis and 2006; PubMed Scopus Google Scholar). However, that HDL does not play a role in TICE. as generally HDL is the for uptake of cholesterol from TICE play no role in the of A by Temel et al. (6Temel R.E. Sawyer J.K. Yu L. Lord C. Degirolamo C. McDaniel A. Marshall S. Wang N. Shah R. Rudel L.L. et al.Biliary sterol secretion is not required for macrophage reverse cholesterol transport.Cell Metab. 2010; 12: 96-102Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar) the of HDL in mice were injected with the cholesterol in the intestinal lumen that TICE can macrophage In et al. N. T. F. D.J. sterol secretion is required for in reverse cholesterol transport in mice.Gastroenterology. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, der Groen A.K. Regulation of cholesterol Cell of Google Scholar) reported that mice with biliary cholesterol secretion fecal excretion of macrophage et al. (12Zhao Y. Pennings M. Vrins C.L. Calpe-Berdiel L. Hoekstra M. Kruijt J.K. Ottenhoff R. Hildebrand R.B. van der Sluis R. Jessup W. et al.Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI.Atherosclerosis. 2011; 218: 314-322Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) the to RCT in the in the was that RCT from WT macrophages was about in both Abca1−/− mice and Abca1−/−×Sr-b1−/− mice. of cholesterol uptake the of RCT data the of Temel et al. but to of et al. of the data we that cholesterol can be to the intestinal lumen both via and TICE. We that cholesterol transport the hepatobiliary route but the cholesterol can be from the liver and be excreted via TICE. The in this does not a into the by which cholesterol is to the enterocyte. We to up a cholesterol transport in cells but to a transport not The reported be directly to the lack and a much biliary cholesterol to secretion with of can be by studies in mice. of biliary secretion is to these we this data for the that direct secretion of cholesterol from blood the intestine into the intestinal lumen of mice of HDL and bile. However, the of the cholesterol donor responsible for delivery of cholesterol to the intestine for secretion via TICE remains to be the intestine an the identification of this in the of TICE the of novel and cholesterol-lowering protein reverse cholesterol transport scavenger receptor transintestinal cholesterol efflux wild-type

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