Selective uptake of cholesteryl esters from apolipoprotein-E-free high-density lipoproteins by rat parenchymal cells <i>in vivo</i> is efficiently coupled to bile acid synthesis

Pieters, Moniek N.; Schouten, Donald; Bakkeren, H. F.; Esbach, B; Brouwer, A.; Knook, D.L.; Berkel, Theo J.C. Van

doi:10.1042/bj2800359

Cited by 67 publications

(63 citation statements)

References 49 publications

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“…Finally, trapping of the mobilized cholesterol in LUVs, which deliver cholesterol to the liver without disturbing genes for cholesterol homeostasis, 41 is far preferable to accelerated HDLmediated sterol delivery to the liver, which can be associated with harmful side effects. 54 For example, although tracer studies [55][56][57][58] suggest that HDL cholesterol can appear in bile, studies of mass flux indicate that the intravenous administration of a cholesterol-rich HDL fraction into rats results in a stimulation of hepatic acyl-CoA:cholesterol acyl transferase and enhanced secretion of cholesterol-rich VLDL, 54 a particle that could potentially be proatherogenic. LUVs, acting with endogenous HDL, may be the preferred therapeutic method to enhance RCT in vivo.…”

Section: Discussionmentioning

confidence: 99%

Remodeling and Shuttling

Rodrigueza

Williams

Rothblat

et al. 1997

ATVB

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In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted ≈20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t½] for UC efflux was ≈50 hours) and human HDL 3 at 25 μg PL per milliliter extracted ≈15% cellular UC label with no change in cellular cholesterol mass (t½ of ≈8 hours). In contrast, the combination of LUVs and HDL 3 extracted over 90% of UC label (t½ of ≈4 hours) and ≈50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other's composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles, remodeled HDL caused faster efflux (t½ ≈4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (≈38% versus ≈15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted ≈20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC label. The label was found almost entirely with the LUVs, suggesting that LUVs continuously stripped the HDL of cellular UC. Second, bidirectional flux studies demonstrated that LUVs blocked the influx of HDL UC label into cells, while the rate of efflux of cellular UC was maintained. These kinetic effects explained the massive net loss of cellular UC to LUVs with HDL. Third, cyclodextrin, an artificial small acceptor that does not acquire PL and hence does not become remodeled, exhibitedCorrespondence to Dr Michael C. Phillips, Department of Biochemistry, Medical College of Pennsylvania and Hahnemann University, 2900 Queen Ln, Philadelphia, PA 19129. Portions of this work were published in abstract form in Abstracts Submitted to the Council on Arteriosclerosis for the 68th Scientific Sesssions of the American Heart Association. 1995:54. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript substantial synergy with LUVs, supporting shuttling. Thus, the presence of large and small acceptors together can overcome intrinsic deficiencies in...

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Section: Discussionmentioning

confidence: 99%

Remodeling and Shuttling

Rodrigueza

Williams

Rothblat

et al. 1997

ATVB

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“…Also, the steroid-synthesizing organs utilize this selective uptake mechanism for CE [8]. Within the liver, only the parenchymal cells are able to perform this process [10]. Interestingly, only the parenchymal cells show increased CEOH uptake as compared with native CE uptake.…”

Section: Discussionmentioning

confidence: 99%

“…In general, clearance of HDL-CE from the blood circulation is caused mainly by the liver and steroid-forming tissues [8][9][10]. The kinetics of liver uptake of CEOH from HDL seems to differ from native CE uptake only in the initial uptake phase, after which the liver uptake increases only slowly, at an equal rate to native HDL-associated CE.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study [10] it was shown that CE from HDL, which were selectively delivered to liver parenchymal cells, were efficiently secreted into bile after conversion into bile acids. In order to assess whether the increased parenchymal cell uptake of HDLassociated [$H]Ch18 : 2-OH is also coupled to an efficient secretion route into bile, rats were equipped with permanent catheters in the bile duct, duodenum and the vena jugularis.…”

Section: Biliary Secretion Of [ 3 H]-radioactivitymentioning

confidence: 99%

“…coworkers [8,9] indicated that CE are taken up selectively by liver parenchymal cells, exceeding uptake of the protein moiety of HDL. Within the liver, only parenchymal cells showed selective uptake, which is directly coupled to efficient biliary secretion of the bile acids formed [10]. A second mechanism for the anti-atherogenic action of HDL is related to its anti-oxidative properties [11].…”

Section: Introductionmentioning

confidence: 99%

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Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells

Fluiter

Vietsch

Biessen

et al. 1996

Biochemical Journal

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Oxidation of low-density lipoprotein (LDL) leads initially to the formation of LDL-associated cholesteryl ester hydroperoxides (CEOOH). LDL-associated CEOOH can be transferred to high-density lipoprotein (HDL), and HDL-associated CEOOH are rapidly reduced to the corresponding hydroxides (CEOH) by an intrinsic peroxidase-like activity. We have now performed in vivo experiments to quantify the clearance rates and to identify the uptake sites of HDL-associated [3H]Ch18:2-OH in rats. Upon injection into rats, HDL-associated [3H]Ch18:2-OH is removed more rapidly from the circulation than HDL-associated [3H]Ch18:2. Two minutes after administration of [3H]Ch18:2-OH-HDL, 19.6±2.6% (S.E.M.; n = 4) of the label was taken up by the liver as compared with 2.4±0.25% (S.E.M.; n = 4) for [3H]Ch18:2-HDL. Organ distribution studies indicated that only the liver and adrenals exhibited preferential uptake of [3H]Ch18:2-OH as compared with [3H]Ch18:2, with the liver as the major site of uptake. A cell-separation procedure, employed 10 min after injection of [3H]Ch18:2-OH-HDL or [3H]Ch18:2-HDL, demonstrated that within the liver only parenchymal cells take up HDL-CE by the selective uptake pathway. Selective uptake by parenchymal cells of [3H]Ch18:2-OH was 3-fold higher than that of [3H]Ch18:2, while Kupffer and endothelial cell uptake of the lipid tracers reflected HDL holoparticle uptake (as analysed with iodinated versus cholesteryl ester-labelled HDL). The efficient uptake of [3H]Ch18:2-OH by parenchymal cells was coupled to a 3-fold increase in rate of radioactive bile acid secretion from [3H]Ch18:2-OH-HDL as compared with [3H]Ch18:2-HDL. In vitro studies with freshly isolated parenchymal cells showed that the association of [3H]Ch18:2-OH-HDL at 37 °C exceeded [3H]Ch18:2-HDL uptake almost 4-fold. Our results indicate that HDL-associated CEOH are efficiently and selectively removed from the blood circulation by the liver in vivo. The selective liver uptake is specifically exerted by parenchymal cells and coupled to a rapid biliary secretion pathway. The liver uptake and biliary secretion route may allow HDL to function as an efficient protection system against potentially atherogenic CEOOH.

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Effects of dietary cholesterol on bile formation and hepatic processing of chylomicron remnant cholesterol in the rat

et al. 1993

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We have studied the coupling between hepatic uptake of chylomicron remnant cholesteryl ester and biliary excretion of cholesterol and bile acids in rats, after feeding them a cholesterol-free (control) or a high-cholesterol diet (1% wt/wt) for 2 wk. We equipped rats with permanent catheters in the bile duct, duodenum and heart to allow experiments in unanesthetized, unrestrained animals. Cholesterol feeding induced a 20% increase in plasma cholesterol concentration, a threefold increase in hepatic bile acid synthesis and a 27% increase in bile acid pool size, whereas biliary excretion of cholesterol was decreased by 50%. The enlarged bile acid pool contained relatively less cholic acid and more chenodeoxycholic acid and muricholic acids. [3H]cholesteryl ester-labeled chylomicron remnants (150 micrograms protein per rat) were injected intracardially, and blood and bile were collected for a period of 22 hr. Plasma disappearance of remnants was significantly delayed by cholesterol feeding, probably caused by competition with diet-induced beta-very low density lipoproteins for hepatic uptake. In control rats biliary excretion of chylomicron remnant-derived radioactivity (50% in free cholesterol and 50% in bile acids) showed an initial peak 1 hr after injection (2.4% dose per hour). A second peak (90% in bile acids), amounting to 1.5% of the dose per hour, appeared 11 hr after injection. Total 22-hr excretion of 3H was 22% of the dose. In cholesterol-fed rats chylomicron remnant-derived radioactivity appeared more rapidly in bile, with a peak 1 hr after injection, amounting to 3.5% of the dose per hour. In this case radioactivity was mainly present as bile acid. Total excretion in 22 hr was 27% of the dose. We conclude that chylomicron remnant uptake by the liver is efficiently coupled to bile acid synthesis and biliary excretion, thus providing an efficient pathway for removal of intestine-derived cholesterol. After cholesterol feeding, chylomicron remnant cholesteryl ester is more efficiently converted to bile acids, a mechanism which may contribute to the resistance of rats to diet-induced elevation of plasma cholesterol. In contrast, biliary excretion in the form of free cholesterol, the second main excretory pathway, is significantly decreased by a high-cholesterol diet.

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Selective uptake of cholesteryl esters from apolipoprotein-E-free high-density lipoproteins by rat parenchymal cells in vivo is efficiently coupled to bile acid synthesis

Cited by 67 publications

References 49 publications

Remodeling and Shuttling

Remodeling and Shuttling

Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells

Effects of dietary cholesterol on bile formation and hepatic processing of chylomicron remnant cholesterol in the rat

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