High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.

Robins, Sander J.; Fasulo, Joan M.

doi:10.1172/jci119170

Cited by 119 publications

(76 citation statements)

References 34 publications

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“…We have further found that when the rat liver is perfused with different classes of plasma lipoproteins that are rich in plant sterols, plant sterol secretion into bile only occurred with the perfusion of HDL. 5 In our present study, we show that a reconstituted HDL particle that includes SIT in addition to its other usual lipid and apoprotein components will also serve as a vehicle for the delivery of plant sterols to the liver for biliary secretion, and that the delivery of SIT to bile from this reconstituted particle is directly proportional to the delivery of plant sterols to bile from native human HDL (Fig. 2).…”

Section: Discussionsupporting

confidence: 50%

“…2), at maximum, the biliary secretion of SIT from rHDL was linearly related to the amount of SIT perfused and to the secretion of plant sterols when native human HDL with a high content of plant sterols were previously perfused. 5 The percentage of SIT that was taken up by the liver and secreted in bile was the same with perfusion of different amounts of SIT and, after 60 minutes, averaged 46.5% Ϯ 5.6% (SD) for the liver and 3.9% Ϯ 1.4% for bile. With increasing amounts of SIT perfused and secreted in bile, biliary UC secretion remained unchanged (data not shown).…”

Section: Resultsmentioning

confidence: 86%

“…Perfusion rates were kept constant at 2.8 to 3.0 mL/min/g liver. rHDL was prepared with: 1) apoproteins from human lipoproteins that were isolated from a plasma pool of about 100 patients by ultracentrifugation at d ϭ 1.060 to 1.21 g/mL; 2) a single molecular species of PC, dipalmitoleoyl-phosphatidylcholine, or 16:1-16:1 PC (Avanti Polar Lipids, Birmingham, AL); 3) a single molecular species of CE, cholesteryl oleate (Nu-Chek-Prep, Elysian, MN); 4) UC that was included as [4-14 C] cholesterol (0.05-0.2 Ci/mol) (DuPont-New England Nuclear, Boston, MA); and 5) SIT that was included as [5, H]SIT (0.1-0.4 Ci/mol) (American Radiolabeled Chemicals, St. Louis, MO). The composition (by weight) of rHDL that was perfused was as follows (mean Ϯ SD of 13 preparations): 43.7% Ϯ 3.1% apoproteins, 27.4% Ϯ 3.9% PC, 23.8% Ϯ 5.7% CE, 2.5% Ϯ 0.3% UC, and 2.6% Ϯ 0.4% SIT.…”

Section: Methodsmentioning

confidence: 99%

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Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

Robins

Fasulo

1999

Hepatology

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Cholesterol is principally excreted from the body in bile as unesterified cholesterol (UC). Using the unesterified plant sterol, sitostanol (SIT), as a nonexchangeable analog for UC, we have found that high-density lipoproteins (HDL), but not low-density lipoproteins, provide a vehicle for the direct delivery of cholesterol to bile. To determine the mechanism for preferential cholesterol transport from HDL to bile, isolated rat livers were perfused with a reconstituted HDL, made with radiolabeled unesterified SIT, UC, and cholesteryl esters (CE). Total biliary sterol secretion was independent of the concentration of HDL added to perfusions, but with increasing HDL-SIT perfused, the proportion of SIT to cholesterol in bile was linearly increased. Biliary SIT secretion was rapid (detected within 2 to 4 minutes after reconstituted HDL was added to perfusions) and was dependent on the immediate presence of SIT in the perfusate, but independent of the amount of SIT that had accumulated in the liver. The ratio of SIT to UC was seven-to ninefold greater in bile than in the liver, consistent with preferential mobilization of membrane sterols delivered from HDL. Although radiolabeled UC as well as SIT was taken up from HDL by the liver and secreted in bile, net UC uptake could not be quantitated because of both UC exchange and a sizable enrichment of HDL with UC mass that approximated the SIT removed during the passage of HDL through the liver. These results are consistent with sterol transport to bile from HDL by a direct plasma membrane pathway and by a mechanism that appears to involve substitution of unesterified (exogenous) sterol from HDL for plasma membrane UC during transport. By this process, HDL can promote reverse cholesterol transport from peripheral tissues to bile, even without an increase in biliary cholesterol secretion. (HEPATOLOGY 1999; 29:1541-1548.)

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Section: Discussionsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

Robins

Fasulo

1999

Hepatology

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“…Because biliary sterols are supposedly derived mainly from HDL cholesterol, 7,8 we next investigated whether the lower free cholesterol liver content in P2Y 13 -KO mice would be translated into altered biliary lipid secretion rates (Table 1). Bile flow and bile acid secretion were somewhat lower following P2Y 13 inactivation.…”

Section: Resultsmentioning

confidence: 99%

P2Y13 Receptor Is Critical for Reverse Cholesterol Transport

et al. 2010

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A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote ''reverse cholesterol transport'' (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y 13 (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y 13 as a target to promote RCT has not been documented. Here, we show that P2Y 13 -deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y 13 -deficient mice. Furthermore, cangrelor, a partial agonist of P2Y 13 , stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BIknockout liver ) but had no effect in P2Y 13 knockout mice, which indicate that P2Y 13 -mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake. Conclusion: These results establish P2Y 13 as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT.

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“…Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans.…”

mentioning

confidence: 99%

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Wang

2005

Hepatology

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It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

show abstract

High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.

Cited by 119 publications

References 34 publications

Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

P2Y13 Receptor Is Critical for Reverse Cholesterol Transport

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

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