Mechanisms of Biliary Lipid Secretion and Their Role in Lipid Homeostasis

ABSTRACT

Bile secretion serves different important functions. First, it is one of the main mechanisms for the disposition of many endogenous and exogenous amphipatic compounds, including drugs, toxins, and waste products. Second, it supplies bile salts to the intestine, which is of crucial importance for the emulsification of dietary lipids. In the last decade considerable progress has been achieved in the elucidation of the process of bile formation. Several key transporters in the canalicular membrane have been identified and characterized. This also holds for the mechanism of biliary lipid secretion, where the lipid translocating function of a P-glycoprotein was found to be indispensable for phospholipid secretion. Concomitantly, it became clear that bile salt-induced lipid secretion is an extremely complex process, in which several steps remain elusive. The production of mice with a specific defect in bilary lipid secretion and the identification of an analogous inherited human disease have made it possible to study the integrated function of biliary lipid secretion in whole body lipid homeostasis. In this review we discuss our current understanding of hepatocanalicular lipid secretion in this context. The pathologic consequences of defects in biliary lipid secretion are discussed in another review in this issue.

KEYWORD

bile - phospholipid - cholesterol

REFERENCES

• 1 Cooper A. Role of the enterohepatic circulation of bile salts in lipoprotein metabolism. In: Ad C, ed. Bile salts: metabolic, pathologic and therapeutic considerations Philadelphia: W.B. Saunders, 1999: 211-229
• 2 Stone B G, Eridison S K, Graig W Y. Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism.  J Clin Invest . 1985;  76 1773-1781
• 3 Nervi F, Marinovic I, Rigotti A. Regulation of biliary cholesterol secretion. Functional relationship between the canalicular and sinusoidal cholesterol secretory pathways in the rat.  J Clin Invest . 1988;  82 1818-1825
• 4 Smit M J, Temmerman A M, Wolters H. Dietary fish oil-induced changes in intrahepatic cholesterol transport and bile acid synthesis in rats.  J Clin Invest . 1991;  88 943-951
• 5 Smit M J, Verkade H J, Havinga R. Dietary fish oil potentiates bile acid-induced cholesterol secretion into bile in rats.  J Lipid Res . 1994;  35 301-310
• 6 Robins S J, Fasulo J M, Leduc R. The transport of lipoprotein cholesterol into bile: A reassessment of kinetic studies in the experimental animal.  Biochim Biophys Acta . 1989;  1004 327-331
• 7 Portal I, Clerc T, Sbarra V. Importance of high-density lipoprotein-phosphatidylcholine in secretion of phospholipid and cholesterol in bile.  Am J Physiol . 1993;  264 G1052-G1056
• 8 Robins S J, Fasulo J M. High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.  J Clin Invest . 1997;  99 380-384
• 9 Brown M S, Goldstein J L. A receptor-mediated pathway for cholesterol homeostasis.  Science . 1986;  232 34-47
• 10 Havel R J, Hamilton R L. Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism.  Hepatology . 1988;  8 1689-1704
• 11 Glass C, Pittman R C, Weinstein D B. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-1 of rat plasma high density lipoprotein: Selective delivery of cholesterol ester to liver, adrenal, and gonad.  Proc Nat Acad Sci USA . 1983;  80 5435-5439
• 12 Glass C, Pittman R C, Civen M. Uptake of high-density lipoprotein-associated apoprotein A-1 and cholesterol esters by 16 tissues of the rat in vivo and by adrenal cells and hepatocytes in vitro.  J Biol Chem . 1985;  260 744-750
• 13 Acton S, Rigotti A, Landschulz K T. Identification of scavenger receptor sr-bi as a high density lipoprotein receptor [see comments].  Science . 1996;  271 518-520
• 14 Rinninger F, Brundert M, Jackle S. Selective uptake of high-density lipoprotein-associated cholesteryl esters by human hepatocytes in primary culture.  Hepatology . 1994;  19 1100-1114
• 15 Trigatti B, Rayburn H, Vinals M. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology.  Proc Natl Acad Sci USA . 1999;  96 9322-9327
• 16 Acton S, Osgood D, Donoghue M. Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population.  Arterioscler Thromb Vasc Biol . 1999;  19 1734-1743
• 17 Arai T, Wang N, Bezouevski M. Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene.  J Biol Chem . 1999;  274 2366-2371
• 18 Kozarsky K F, Donahee M H, Rigotti A. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels.  Nature . 1997;  387 414-417
• 19 Sehayek E, Ono J G, Shefer S. Biliary cholesterol excretion: A novel mechanism that regulates dietary cholesterol absorption.  Proc Natl Acad Sci USA . 1998;  95 10194-10199
• 20 Empen K, Lange K, Stange E F. Newly synthesized cholesterol in human bile and plasma: Quantitation by mass isotopomer distribution analysis.  Am J Physiol . 1997;  272 G367-G373
• 21 Kent C. CTP:phosphocholine cytidylyltransferase.  Biochim Biophys Acta . 1997;  1348 79-90
• 22 Vance D E, Walkey C J, Cui Z. Phosphatidylethanolamine N-methyltransferase from liver.  Biochim Biophys Acta . 1997;  1348 142-150
• 23 Cui Z, Vance J E, Chen M H. Cloning and expression of a novel phosphatidylethanolamine N-methyltransferase. A specific biochemical and cytological marker for a unique membrane fraction in rat liver.  J Biol Chem . 1993;  268 16655-16663
• 24 Sundler R, Akesson B. Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates.  J Biol Chem . 1975;  250 3359-3367
• 25 Walkey C J, Donohue L R, Bronson R. Disruption of the murine gene encoding phosphatidylethanolamine N-methyltransferase.  Proc Natl Acad Sci USA . 1997;  94 12880-12885
• 26 Walkey C J, Yu L, Agellon L B. Biochemical and evolutionary significance of phospholipid methylation.  J Biol Chem . 1998;  273 27043-27046
• 27 Patton G M, Fasulo J M, Robins S J. Hepatic phosphatidylcholines: Evidence for synthesis in the rat by extensive reutilization of endogenous acylglycerides.  J Lipid Res . 1994;  35 1211-1221
• 28 Coleman R, Rahman K. Lipid flow in bile formation.  Biochim Biophys Acta . 1992;  1125 113-133
• 29 Mazer N A, Carey M C. Mathematical model of biliary lipid secretion: A quantitative analysis of physiological and biochemical data from man and other species.  J Lipid Res . 1984;  25 932-953
• 30 Elferink R P, Tytgat G N, Groen A K. Hepatic canalicular membrane 1: The role of mdr2 P-glycoprotein in hepatobiliary lipid transport.  FASEB J . 1997;  11 19-28
• 31 Coleman R, Rahman K, Kan K S. Retrograde intrabiliary injection of amphipathic materials causes phospholipid secretion into bile.  Biochem J . 1989;  258 17-22
• 32 Evens W H. A biochemical dissection of the functional polarity of the plasma membrane of the hepatocyte.  Biochim Biophys Acta . 1980;  604 27-64
• 33 Yousef I M, Barnwell S, Gratton F. Liver cell membrane solubilization may control maximum secretory rate of cholic acid in the rat.  Am J Physiol . 1987;  252 G84-G91.
• 34 Smit J JM, Schinkel A H, Oude Elferink R PJ. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell . 1993;  75 451-462
• 35 Oude Elferink R PJ, Smit J JM, Schinkel A H. The physiological role of mdr2 P-glycoprotein in hepatobiliary phospholipid transport.  In: Keppler D, Jungermann K, eds. Transport in the liver Dordrecht: Kluwer, 1994: 204-213
• 36 Oude Elferink R PJ, Ottenhoff R, van Wijland M. Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein.  J Lipid Res . 1996;  37 1065-1075
• 37 Somjen G J, Gilat T. A non-micellar mode of cholesterol transport in human bile.  FEBS Lett . 1983;  61 265-268
• 38 Pattinson N R. Solubilisation of cholesterol in human bile.  FEBS Lett . 1985;  181 339-342
• 39 Lee S P, Park H Z, Madani H. Partial characterization of a nonmicellar system of cholesterol solubilization in bile.  Am J Physiol . 1987;  252 G374-G384
• 40 Ulloa N, Garrido J, Nervi F. Ultracentrifugal isolation of vesicular carriers of biliary chlesterol in native human and rat bile.  Hepatology . 1987;  7 235-244
• 41 Crawford J M, Möckel G-M, Crawford A R. Imaging biliary lipid secretion in the rat: Ultrastructural evidence for vesiculation of the hepatocyte canalicular membrane.  J Lipid Res . 1995;  36 2147-2163
• 42 Crawford A R, Smith A J, Hatch V C. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy.  J Clin Invest . 1997;  100 2562-2567
• 43 Ruetz S, Gros P. Phosphatidylcholine translocase: A physiological role for the mdr2 gene.  Cell . 1994;  77 1071-1082
• 44 Smith A J, Timmermans-Hereijgers J LPM, Roelofsen B. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice.  FEBS Lett . 1994;  354 263-266
• 45 van Helvoort A, Smith A J, Sprong H. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-gp specifically translocates phosphatidylcholine.  Cell . 1996;  87 507-517
• 46 Nies A T, Gatmaitan Z, Arias I M. Atp-dependent phosphatidylcholine translocation in rat liver canalicular plasma membrane vesicles.  J Lipid Res . 1996;  37 1125-1136
• 47 Velardi A LM, Groen A K, Oude Elferink R PJ. Cell type-dependent effect of phospholipid and cholesterol on bile salt cytotoxicity.  Gastroenterology . 1991;  101 457-464
• 48 Eckhardt E RM, Moschetta A, Renooij W. Asymmetric distribution of phosphatidylcholine and sphingomyelin between micellar and vesicular phases: Potential implications for canalicular bile formation.  J Lipid Res . 1999;  40 2022-2033
• 49 Demel R A, Jansen J W, van Dijck P W. The preferential interaction of cholesterol with different classes of phospholipids.  Biochim Biophys Acta . 1977;  465 1-10
• 50 Slotte J P. Lateral domain formation in mixed monolayers containing cholesterol and dipalmitoylphosphatidylcholine or N-palmitoylsphingomyelin.  Biochim Biophys Acta . 1995;  1235 419-427
• 51 Mattjus P, Bittman R, Vilcheze C. Lateral domain formation in cholesterol/phospholipid monolayers as affected by the sterol side chain conformation.  Biochim Biophys Acta . 1995;  1240 237-247
• 52 Evans W, Kremmer T, Culvenor J. Role of membranes in bile formation. Comparison of the composition of bile and a liver-canalicular plasma membrane subfraction.  Biochem J . 1976;  154 589-595
• 53 Meier P J, Sztul E S, Reuben A. Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver.  J Cell Biol . 1984;  98 991-1000
• 54 Nibbering C P, Carey M C. Sphingomyelins of rat liver: Biliary enrichment with molecular species containing 16:0 fatty acids as compared to canalicular-enriched plasma membranes.  J Membr Biol . 1999;  167 165-171
• 55 Cohen D E, Leonard M R, Carey M C. In vitro evidence that phospholipid secretion into bile may be coordinated intracellularly by the combined actions of bile salts and the specific phosphatidylcholine transfer protein of liver.  Biochemistry . 1994;  33 9975-9980
• 56 Cohen D E, Green R M. Cloning and characterization of a cDNA encoding the specific phosphatidylcholine transfer protein from bovine liver.  Gene . 1995;  163 327-328
• 57 Wirtz K WA, Kamp H H, van Deenen L LM. Isolation of a protein from beef liver which specifically stimulates the exchange of phosphatidylcholine.  Biochim Biophys Acta . 1972;  274 606-617
• 58 Wirtz K WA. Phospholipid transfer proteins revisited [review].  Biochem J . 1997;  324 353-360
• 59 LaMorte W W, Booker M L, Kay S. Determinants of the selection of phosphatidylcholine molecular species of secretion into bile in the rat.  Hepatology . 1998;  28 631-637
• 60 van Helvoort A, de Brouwer A, Ottenhoff R. Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces.  Proc Natl Acad Sci USA . 1999;  96 11501-11506
• 61 Noland B J, Arebalo R E, Hansbury E. Purification ad properties of sterol carrier protein 2.  J Biol Chem . 1980;  255 4282-4289
• 62 Bloj B, Zilversmit D B. Rat liver proteins capable of transferring phosphatidylethanollamine. Purification and transfer activity for other phospholipids and cholesterol.  J Biol Chem . 1977;  252 1613-1619
• 63 Stolowich N J, Frolov A, Atshaves B. The sterol carrier protein-2 fatty acid binding site: An NMR, circular dichroic, and fluorescence spectroscopic determination.  Biochemistry . 1997;  36 1719-1729
• 64 Seedorf U, Raabe M, Ellinghaus P. Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.  Genes Dev . 1998;  12 1189-1201
• 65 Keller G A, Scallen T J, Clarke D. Subcellular localization of sterol carrier protein-2 in rat hepatocytes: Its primary localization to peroxisomes.  J Cell Biol . 1989;  108 1353-1361
• 66 Ossendorp B C, Wirtz K W. The non-specific lipid-transfer protein (sterol carrier protein 2) and its relationship to peroxisomes.  Biochimie . 1993;  75 191-200
• 67 Fuchs M, Lammert F, Wang D Q. Sterol carrier protein 2 participates in hypersecretion of biliary cholesterol during gallstone formation in genetically gallstone-susceptible mice.  Biochem J . 1998;  336 33-37
• 68 Puglielli L, Rigotti A, Amigo L. Modulation of intrahepatic cholesterol trafficking-evidence by in vivo antisense treatment for the involvement of sterol carrier protein-2 in newly synthesized cholesterol transport into rat bile.  Biochem J . 1996;  317 681-687
• 69 Crawford J M, Berken C A, Gollan J L. Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: Implications for intracellular vesicular transport.  J Lipid Res . 1988;  29 144-156
• 70 Casu A, Camogliano L. Glycerophospholipids and cholesterol composition of bile in bile-fistula rats treated with monensin.  Biochim Biophys Acta . 1990;  1043 113-115
• 71 Reynier M O, Abouhashieh I, Crotte C. Monensin action on the Golgi complex in perfused rat liver evidence against bile salt vesicular transport.  Gastroenterology . 1992;  102 2024-2032
• 72 Van M eer, Simons K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells.  EMBO J . 1986;  5 1455-1464
• 73 Robins S J, Fasulo J M. 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.  Hepatology . 1999;  29 1541-1548
• 74 Zhang X, Collins K I, Greenberger L M. Functional evidence that transmembrane 12 and the loop between transmembrane 11 and 12 form part of the drug-binding domain in P-glycoprotein encoded by MDR1.  J Biol Chem . 1995;  270 5441-5448.
• 75 Currier S J, Kane S E, Willingham M C. Identification of residues in the first cytoplasmic loop of P-glycoprotein involved in the function of chimeric human MDR1-MDR2 transporters.  J Biol Chem . 1992;  267 25153-25159
• 76 Buschman E, Gros P. Functional analysis of chimeric genes obtained by exchanging homologous domains of the mouse mdr1 and mdr2 genes.  Mol Cell Biol . 1991;  11 595-603
• 77 Zhou Y, Gottesman M M, Pastan I. Domain exchangeability between the multidrug transporter (MDR1) and phosphatidylcholine flippase (MDR2).  Mol Pharmacol . 1999;  56 997-1004
• 78 Zhou Y, Gottesman M M, Pastan I. Studies of human MDR1-MDR2 chimeras demonstrate the functional exchangeability of a major transmembrane segment of the multidrug transporter and phosphatidylcholine flippase.  Mol Cell Biol . 1999;  19 1450-1459
• 79 Smith A J. The substrate specificites of the human MDR1 and MDR3 P-glycoproteins. Amsterdam: Netherlands Cancer Inst 1998: 133
• 80 Frijters C MG, Ottenyhoff R, Vanwijland M JA. Regulation of mdr2 p-glycoprotein expression by bile salts.  Biochem J . 1997;  321 389-395
• 81 Carrella M, Feldman D, Cogoi S. Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an increased biosynthesis in the pravastatin-treated rat.  Hepatology . 1999;  29 1825-1832
• 82 Hooiveld G JEJ, Vos T A, Scheffer G L. 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins) induce haptic expression of the phospholipid translocase mdr2 in rats.  Gastroenterology . 1999;  117 678-687
• 83 Grundy S M. Absorption and metabolism of dietary cholesterol.  Annu Rev Nutr . 1983;  3 71-96
• 84 Westergaard H, Dietschy J M. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell.  J Clin Invest . 1976;  58 97-108
• 85 Voshol P J, Havinga R, Wolters H. Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 p-glycoprotein-deficient mice.  Gastroenterology . 1998;  114 1024-1034
• 86 Voshol P J, Minich D M, Havinga R. Postprandial chylomicron formation and fat absorption in multidrug resistance gene 2 P-glycoprotein-deficient mice.  Gastroenterology . 2000;  118 173-182
• 87 Whitington P F, Freese D K, Alonso E M. Clinical and biochemical findings in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 134-141
• 88 Alonso E M, Snover D C, Montag A. Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 128-133
• 89 Kattermann R, Creutzfeldt W. The effect of experimental cholestasis on the negative feedback regulation of cholesterol synthesis in rat liver.  Scand J Gastroenterol . 1970;  5 337-342
• 90 Harry D S, Dini M, McIntyre N. Effect of cholesterol feeding and biliary obstruction on hepatic cholesterol biosynthesis in the rat.  Biochim Biophys Acta . 1973;  296 209-220
• 91 Cooper A D, Ockner R D. Studies of hepatic cholesterol synthesis in experimental acute biliary obstruction.  Gastroenterology . 1974;  66 586-595
• 92 Dueland S, Reichen J, Everson G T. Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats.  Biochem J . 1991;  280 373-377
• 93 McIntyre N, Harry D S, Pearson A J. The hypercholesterolaemia of obstructive jaundice.  Gut . 1975;  16 379-391
• 94 Walli A K, Seidel D. Role of lipoprotein-X in the pathogenesis of cholestatic hypercholesterolemia. Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat.  J Clin Invest . 1984;  74 867-879
• 95 Ahrens E H, Kunkel H G. The relationship between serum lipids and skin xanthomata in eighteen patients with primary biliary cirrhosis.  J Clin Invest . 1949;  28 1565-1574