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Lipid Transport in the Lactating Mammary Gland

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Mammalian cells depend on phospholipid (PL) and fatty acid (FA) transport to maintain membrane structure and organization, and to fuel and regulate cellular functions. In mammary glands of lactating animals, copious milk secretion, including large quantities of lipid in some species, requires adaptation and integration of PL and FA synthesis and transport processes to meet secretion demands. At present few details exist about how these processes are regulated within the mammary gland. However, recent advances in our understanding of the structural and molecular biology of membrane systems and cellular lipid trafficking provide insights into the mechanisms underlying the regulation and integration of PL and FA transport processes the lactating mammary gland. This review discusses the PL and FA transport processes required to maintain the structural integrity and organization of the mammary gland and support its secretory functions within the context of current molecular and cellular models of their regulation.

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Abbreviations

ABC:

ATP-binding cassette

ACSL:

Acyl-coA synthetase

ApoA1:

Apolipoprotein A1

ATP:

Adenosine triphosphate

Cept:

Choline-ethanolamine phosphotransferase

CER:

Common endosome recycling

CERT:

Ceramide transport protein

CLD:

Cytoplasmic lipid droplets

Cpt:

CDP-choline phosphotransferase

DAG:

Diacylglycerol

FA:

Fatty acid

FAT:

Fatty acid translocase

FATP:

Fatty acid transport protein

ER:

Endoplasmic reticulum

LCFA:

Long-chain fatty acids

LPL:

Lipoprotein lipase

LTP:

Lipid transport proteins

MAM:

Mitochondrial associated membranes

MFG:

Milk fat globule

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

Pemt:

Phosphatidylethanolamine N-methyltransferase

PI:

Phosphatidylinositol

PL:

Phospholipid

PS:

Phosphatidylserine

PSS1:

Phosphotidyserine synthase 1

PSS2:

Phosphotidyserine synthase 2

SL:

Sphingolipids

SM:

Sphingomyelin

SV:

Secretory vesicle

References

  1. Federovitch CM et al. The dynamic ER: experimental approaches and current questions. Curr Opin Cell Biol. 2005;17:409–14.

    Article  CAS  PubMed  Google Scholar 

  2. Coleman JA et al. Mammalian P4-ATPases and ABC transporters and their role in phospholipid transport. Biochim Biophys Acta. 2013;1831:555–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Anderson SM et al. Key stages in mammary gland development. Secretory activation in the mammary gland: it’s not just about milk protein synthesis! Breast Cancer Res. 2007;9:204.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Mashek DG et al. Long-chain acyl-CoA synthetases and fatty acid channeling. Futur Lipidol. 2007;2:465–76.

    Article  CAS  Google Scholar 

  5. Ikonen E, Simons K. Protein and lipid sorting from the trans-Golgi network to the plasma membrane in polarized cells. Semin Cell Dev Biol. 1998;9:503–9.

    Article  CAS  PubMed  Google Scholar 

  6. Hollmann KH. Cytology and fine structure of the mammary gland. In: Larson BL, Smith VR, editors. Lactation. New York: Academic; 1974. p. 3–95.

    Google Scholar 

  7. Wooding FBP. Comparative mammary fine structure. In: Peaker M, editor. Comparative aspects of lactation. London: Academic; 1977. p. 1–41.

    Google Scholar 

  8. Clermont Y et al. Structure of the Golgi apparatus in stimulated and nonstimulated acinar cells of mammary glands of the rat. Anat Rec. 1993;237:308–17.

    Article  CAS  PubMed  Google Scholar 

  9. Ron D, Hampton RY. Membrane biogenesis and the unfolded protein response. J Cell Biol. 2004;167:23–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Mather IH, Keenan TW. Origin and secretion of milk lipids. J Mammary Gland Biol Neoplasia. 1998;3:259–73.

    Article  CAS  PubMed  Google Scholar 

  11. McManaman JL et al. Molecular determinants of milk lipid secretion. J Mammary Gland Biol Neoplasia. 2007;12:259–68.

    Article  PubMed  Google Scholar 

  12. Folsch H et al. Taking the scenic route: biosynthetic traffic to the plasma membrane in polarized epithelial cells. Traffic. 2009;10:972–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Monks J, McManaman JL. Secretion and fluid transport mechanisms in the mammary gland. In: Zibadi S et al., editors. Handbook of dietary and nutritional aspects of human breast milk. Wageningen: Wageningen Academic Publishers; 2013. p. 35–56.

    Chapter  Google Scholar 

  14. Holthuis JC, Levine TP. Lipid traffic: floppy drives and a superhighway. Nat Rev Mol Cell Biol. 2005;6:209–20.

    Article  CAS  PubMed  Google Scholar 

  15. McManaman JL. Milk lipid secretion: recent biomolecular aspects. Biomol Concepts. 2012;3:581–91.

    Article  PubMed Central  Google Scholar 

  16. van Meer G et al. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9:112–24.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Jelsema CL, Morre DJ. Distribution of phospholipid biosynthetic enzymes among cell components of rat liver. J Biol Chem. 1978;253:7960–71.

    CAS  PubMed  Google Scholar 

  18. Henneberry AL et al. The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity. Mol Biol Cell. 2002;13:3148–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Vance JE. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res. 2008;49:1377–87.

    Article  CAS  PubMed  Google Scholar 

  20. Fagone P, Jackowski S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res. 2009;50(Suppl):S311–316.

    PubMed Central  PubMed  Google Scholar 

  21. Vance DE. Physiological roles of phosphatidylethanolamine N-methyltransferase. Biochim Biophys Acta. 2013;1831:626–32.

    Article  CAS  PubMed  Google Scholar 

  22. Osman C et al. Making heads or tails of phospholipids in mitochondria. J Cell Biol. 2011;192:7–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Yang EK et al. Rat and human mammary tissue can synthesize choline moiety via the methylation of phosphatidylethanolamine. Biochem J. 1988;256:821–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Vance DE, de Kruijff B. The possible functional significance of phosphatidylethanolamine methylation. Nature. 1980;288:277–9.

    Article  CAS  PubMed  Google Scholar 

  25. Zborowski J et al. Phosphatidylserine decarboxylase is located on the external side of the inner mitochondrial membrane. FEBS Lett. 1983;157:179–82.

    Article  CAS  PubMed  Google Scholar 

  26. Vance JE, Tasseva G. Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim Biophys Acta. 2013;1831:543–54.

    Article  CAS  PubMed  Google Scholar 

  27. Voelker DR. Organelle biogenesis and intracellular lipid transport in eukaryotes. Microbiol Rev. 1991;55:543–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Vance JE. Newly made phosphatidylserine and phosphatidylethanolamine are preferentially translocated between rat liver mitochondria and endoplasmic reticulum. J Biol Chem. 1991;266:89–97.

    CAS  PubMed  Google Scholar 

  29. Sleight RG, Pagano RE. Rapid appearance of newly synthesized phosphatidylethanolamine at the plasma membrane. J Biol Chem. 1983;258:9050–8.

    CAS  PubMed  Google Scholar 

  30. Vance JE. Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem. 1990;265:7248–56.

    CAS  PubMed  Google Scholar 

  31. Agranoff BW et al. The enzymatic synthesis of inositol phosphatide. J Biol Chem. 1958;233:1077–83.

    CAS  PubMed  Google Scholar 

  32. Bell RM et al. Lipid topogenesis. J Lipid Res. 1981;22:391–403.

    CAS  PubMed  Google Scholar 

  33. Cockcroft S, Carvou N. Biochemical and biological functions of class I phosphatidylinositol transfer proteins. Biochim Biophys Acta. 2007;1771:677–91.

    Article  CAS  PubMed  Google Scholar 

  34. Kim YJ et al. A highly dynamic ER-derived phosphatidylinositol-synthesizing organelle supplies phosphoinositides to cellular membranes. Dev Cell. 2011;21:813–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Hanada K et al. CERT and intracellular trafficking of ceramide. Biochim Biophys Acta. 2007;1771:644–53.

    Article  CAS  PubMed  Google Scholar 

  36. Hanada K. Discovery of the molecular machinery CERT for endoplasmic reticulum-to-Golgi trafficking of ceramide. Mol Cell Biochem. 2006;286:23–31.

    Article  CAS  PubMed  Google Scholar 

  37. Daleke DL. Phospholipid flippases. J Biol Chem. 2007;282:821–5.

    Article  CAS  PubMed  Google Scholar 

  38. Lagace TA, Ridgway ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochim Biophys Acta. 2013;1833:2499–510.

    Article  CAS  PubMed  Google Scholar 

  39. Pilarska M et al. Properties and topology of enzymes methylating phosphatidylethanolamine to phosphatidylcholine in sarcoplasmic reticulum. Int J Biochem. 1987;19:705–11.

    Article  CAS  PubMed  Google Scholar 

  40. Bishop WR, Bell RM. Assembly of the endoplasmic reticulum phospholipid bilayer: the phosphatidylcholine transporter. Cell. 1985;42:51–60.

    Article  CAS  PubMed  Google Scholar 

  41. Kaplan MR, Simoni RD. Intracellular transport of phosphatidylcholine to the plasma membrane. J Cell Biol. 1985;101:441–5.

    Article  CAS  PubMed  Google Scholar 

  42. Muthusamy BP et al. Linking phospholipid flippases to vesicle-mediated protein transport. Biochim Biophys Acta. 2009;1791:612–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Seigneuret M, Devaux PF. ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: relation to shape changes. Proc Natl Acad Sci U S A. 1984;81:3751–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Devaux PF, Morris R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic. 2004;5:241–6.

    Article  CAS  PubMed  Google Scholar 

  45. Yabas M et al. ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes. Nat Immunol. 2011;12:441–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Pomorski T et al. Tracking down lipid flippases and their biological functions. J Cell Sci. 2004;117:805–13.

    Article  CAS  PubMed  Google Scholar 

  47. Gottesman MM et al. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.

    Article  CAS  PubMed  Google Scholar 

  48. Mani O et al. Expression, localization, and functional model of cholesterol transporters in lactating and nonlactating mammary tissues of murine, bovine, and human origin. Am J Physiol Regul Integr Comp Physiol. 2010;299:R642–654.

    Article  CAS  PubMed  Google Scholar 

  49. Mani O et al. Identification of ABCA1 and ABCG1 in milk fat globules and mammary cells–implications for milk cholesterol secretion. J Dairy Sci. 2011;94:1265–76.

    Article  CAS  PubMed  Google Scholar 

  50. Ontsouka EC et al. Characteristics and functional relevance of apolipoprotein-A1 and cholesterol binding in mammary gland tissues and epithelial cells. PLoS One. 2013;8:e70407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. D’Alessandro A et al. Human milk proteins: an interactomics and updated functional overview. J Proteome Res. 2010;9:3339–73.

    Article  PubMed  Google Scholar 

  52. Hunziker W, Kraehenbuhl JP. Epithelial transcytosis of immunoglobulins. J Mammary Gland Biol Neoplasia. 1998;3:287–302.

    Article  CAS  PubMed  Google Scholar 

  53. Monks J, Neville MC. Albumin transcytosis across the epithelium of the lactating mouse mammary gland. J Physiol. 2004;560:267–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Grant BD, Donaldson JG. Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol. 2009;10:597–608.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Golachowska MR et al. Recycling endosomes in apical plasma membrane domain formation and epithelial cell polarity. Trends Cell Biol. 2010;20:618–26.

    Article  CAS  PubMed  Google Scholar 

  56. Welsch U et al. Internalization of ferritin-concanavalin A by the lactating mammary cell in vivo. Cell Tissue Res. 1984;235:433–8.

    Article  CAS  PubMed  Google Scholar 

  57. Monks J et al. A lipoprotein-containing particle is transferred from the serum across the mammary epithelium into the milk of lactating mice. J Lipid Res. 2001;42:686–96.

    CAS  PubMed  Google Scholar 

  58. Mousley CJ et al. The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking. Biochim Biophys Acta. 2007;1771:727–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Wirtz KW et al. Properties and possible function of phosphatidylinositol-transfer proteins. Biotechnol Appl Biochem. 1990;12:485–8.

    CAS  PubMed  Google Scholar 

  60. de Vries KJ et al. An isoform of the phosphatidylinositol-transfer protein transfers sphingomyelin and is associated with the Golgi system. Biochem J. 1995;310(Pt 2):643–9.

    PubMed Central  PubMed  Google Scholar 

  61. Dickeson SK et al. Isolation and sequence of cDNA clones encoding rat phosphatidylinositol transfer protein. J Biol Chem. 1989;264:16557–64.

    CAS  PubMed  Google Scholar 

  62. Hanada K. Intracellular trafficking of ceramide by ceramide transfer protein. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86:426–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Schwertfeger KL et al. Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J Lipid Res. 2003;44:1100–12.

    Article  CAS  PubMed  Google Scholar 

  64. Tauchi-Sato K et al. The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition. J Biol Chem. 2002;277:44507–12.

    Article  CAS  PubMed  Google Scholar 

  65. Wu CC et al. Proteomics reveal a link between the endoplasmic reticulum and lipid secretory mechanisms in mammary epithelial cells. Electrophoresis. 2000;21:3470–82.

    Article  CAS  PubMed  Google Scholar 

  66. McManaman JL et al. Secretion and fluid transport mechanisms in the mammary gland: comparisons with the exocrine pancreas and the salivary gland. J Mammary Gland Biol Neoplasia. 2006;11:249–68.

    Article  PubMed  Google Scholar 

  67. Walther TC, Farese Jr RV. The life of lipid droplets. Biochim Biophys Acta. 2009;1791:459–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Stein O, Stein Y. Lipid synthesis, intracellular transport, and secretion. II. Electron microscopic radioautographic study of the mouse lactating mammary gland. J Cell Biol. 1967;34:251–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Bionaz M, Loor JJ. ACSL1, AGPAT6, FABP3, LPIN1, and SLC27A6 are the most abundant isoforms in bovine mammary tissue and their expression is affected by stage of lactation. J Nutr. 2008;138:1019–24.

    CAS  PubMed  Google Scholar 

  70. Han LQ et al. mRNA abundance and expression of SLC27A, ACC, SCD, FADS, LPIN, INSIG, and PPARGC1 gene isoforms in mouse mammary glands during the lactation cycle. Genet Mol Res. 2010;9:1250–7.

    Article  CAS  PubMed  Google Scholar 

  71. Bionaz M, Loor JJ. Gene networks driving bovine milk fat synthesis during the lactation cycle. BMC Genomics. 2008;9:366.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Neville MC, Picciano MF. Regulation of milk lipid secretion and composition. Annu Rev Nutr. 1997;17:159–83.

    Article  CAS  PubMed  Google Scholar 

  73. Goldberg IJ et al. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. J Lipid Res. 2009;50(Suppl):S86–90.

    PubMed Central  PubMed  Google Scholar 

  74. Hamilton JA. New insights into the roles of proteins and lipids in membrane transport of fatty acids. Prostaglandins Leukot Essent Fat Acids. 2007;77:355–61.

    Article  CAS  Google Scholar 

  75. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20:72–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Schaffer JE. Fatty acid transport: the roads taken. Am J Physiol Endocrinol Metab. 2002;282:E239–246.

    CAS  PubMed  Google Scholar 

  77. Abumrad NA et al. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J Biol Chem. 1993;268:17665–8.

    CAS  PubMed  Google Scholar 

  78. Acton SL et al. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994;269:21003–9.

    CAS  PubMed  Google Scholar 

  79. Febbraio M, Silverstein RL. CD36: implications in cardiovascular disease. Int J Biochem Cell Biol. 2007;39:2012–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Greenwalt DE, Mather IH. Characterization of an apically derived epithelial membrane glycoprotein from bovine milk, which is expressed in capillary endothelia in diverse tissues. J Cell Biol. 1985;100:397–408.

    Article  CAS  PubMed  Google Scholar 

  81. Greenwalt DE et al. PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell DC36 (GPIV). Biochemistry. 1990;29:7054–9.

    Article  CAS  PubMed  Google Scholar 

  82. DeFilippis RA et al. CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov. 2012;2:826–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Watkins PA. Very-long-chain acyl-CoA synthetases. J Biol Chem. 2008;283:1773–7.

    Article  CAS  PubMed  Google Scholar 

  84. Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med (Maywood). 2008;233:507–21.

    Article  CAS  Google Scholar 

  85. Stahl A. A current review of fatty acid transport proteins (SLC27). Pflugers Arch. 2004;447:722–7.

    Article  CAS  PubMed  Google Scholar 

  86. Palmer CA et al. Transgenic mice expressing recombinant human protein C exhibit defects in lactation and impaired mammary gland development. Transgenic Res. 2003;12:283–92.

    Article  CAS  PubMed  Google Scholar 

  87. McManaman JL et al. Regulation of milk lipid formation and secretion in the mouse mammary gland. Adv Exp Med Biol. 2004;554:263–79.

    Article  CAS  PubMed  Google Scholar 

  88. Welte MA. Fat on the move: intracellular motion of lipid droplets. Biochem Soc Trans. 2009;37:991–6.

    Article  CAS  PubMed  Google Scholar 

  89. Orlicky DJ et al. Dynamics and molecular determinants of cytoplasmic lipid droplet clustering and dispersion. PLoS One. 2013;8:e66837.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Patton S et al. The supression of milk fat globule secretion by clochicine: an effect coupled to inhibition of exocytosis. Biochim Biophys Acta. 1977;499:404–10.

    Article  CAS  PubMed  Google Scholar 

  91. Lemay DG et al. Gene regulatory networks in lactation: identification of global principles using bioinformatics. BMC Syst Biol. 2007;1:56.

    Article  PubMed Central  PubMed  Google Scholar 

  92. Bartz R et al. Lipidomics reveals that adiposomes store ether lipids and mediate phospholipid traffic. J Lipid Res. 2007;48:837–47.

    Article  CAS  PubMed  Google Scholar 

  93. Contarini G, Povolo M. Phospholipids in milk fat: composition, biological and technological significance, and analytical strategies. Int J Mol Sci. 2013;14:2808–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Supported by National Institutes of Health grants 5R01-HD045962, 1R01-HD075285 and P01-HD38129.

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McManaman, J.L. Lipid Transport in the Lactating Mammary Gland. J Mammary Gland Biol Neoplasia 19, 35–42 (2014). https://doi.org/10.1007/s10911-014-9318-8

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