Characterization of phospholipids in insulin secretory granules and mitochondria in pancreatic beta cells and their changes with glucose stimulation

Journal of Biological Chemistry

Volumn 290, Issue 17, 2015, Pages 11075-11092

  MacDonald, Michael J ^a   Ade, Lacmbouh ^b   Ntambi, James M ^b   Ansari, Israr Ul H ^a   Stoker, Scott W ^a  

^a UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

^b UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL MEMBRANES; CELLS; COUPLINGS; CYTOLOGY; GLUCOSE; GRANULATION; INSULIN; LIPID BILAYERS; LIPIDS; MEMBRANES; PHOSPHOLIPIDS; PROTEINS; UNSATURATED FATTY ACIDS;

NEGATIVELY CHARGED; PANCREATIC BETA CELLS; PHOSPHATIDYL CHOLINE; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLINOSITOL; PHOSPHATIDYLSERINE; SECRETORY GRANULES; SECRETORY VESICLES;

FATTY ACIDS;

GLUCOSE; INSULIN; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLINOSITOL; PHOSPHATIDYLSERINE; PHOSPHOLIPID; SHORT CHAIN FATTY ACID; SNARE PROTEIN; SPHINGOMYELIN; UNSATURATED FATTY ACID; SWEETENING AGENT;

ANIMAL CELL; ARTICLE; CELL GRANULE; CELL INTERACTION; CELL MEMBRANE FLUIDITY; CONTROLLED STUDY; EXOCYTOSIS; HUMAN; HUMAN CELL; INSULIN RELEASE; INSULIN SECRETORY GRANULE; LIPID ANALYSIS; LIPID COMPOSITION; MITOCHONDRION; NONHUMAN; PANCREAS ISLET BETA CELL; PHOSPHOLIPID BILAYER; PRIORITY JOURNAL; PROTEIN INTERACTION; SECRETORY VESICLE; SYNAPSE VESICLE; ANIMAL; CELL LINE; CYTOLOGY; DRUG EFFECTS; METABOLISM; MOUSE; SECRETION (PROCESS);

ANIMALS; CELL LINE; EXOCYTOSIS; GLUCOSE; INSULIN; INSULIN-SECRETING CELLS; MICE; MITOCHONDRIA; PHOSPHOLIPIDS; SECRETORY VESICLES; SWEETENING AGENTS;

EID: 84928402177     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.628420     Document Type: Article

References (87)

1. Corkey, B. E., Deeney, J. T., Yaney, G. C., Tornheim, K., and Prentki, M., (2000) The role of long-chain fatty acyl-CoA esters in beta cell signal transduction. J. Nutr. 130, 299S-304S
2. Farfari, S., Schulz, V., Corkey, B., and Prentki, M. (2000) Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion. Diabetes 49, 718-726
3. Flamez, D., Berger, V., Kruhøffer, M., Orntoft, T., Pipeleers, D., and Schuit, F. C. (2002) Critical role for cataplerosis via citrate in glucose-regulated insulin release. Diabetes 51, 2018-2024
4. MacDonald, M. J., Fahien, L. A., Brown, L. J., Hasan, N. M., Buss, J. D., and Kendrick, M. A. (2005) Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. Am. J. Physiol. Endocrinol. Metab. 288, E1-E15
5. MacDonald, M. J., Smith, A. D., 3rd, Hasan, N. M., Sabat, G., and Fahien, L. A. (2007) Feasibility of pathways for transfer of acyl groups from mitochondria to the cytosol to form short chain acyl CoAs in the pancreatic beta cell. J. Biol. Chem. 282, 30596-30606
6. MacDonald, M. J. (2007) Synergistic potent insulin release by combinations of weak secretagogues in pancreatic islets and INS-1 cells. J. Biol. Chem. 282, 6043-6052
7. Muoio, D. M., and Newgard, C. B. (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 193-205
8. Jitrapakdee, S., Wutthisathapornchai, A., Wallace, J. C., and MacDonald, M. J. (2010) Regulation of insulin secretion: role of mitochondrial signaling. Diabetologia 53, 1019-1032
9. Prentki, M., Matschinsky, F. M., and Madiraju, S. R. (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 18, 162-185
10. Lorenz, M. A., El Azzouny, M. A., Kennedy, R. T., and Burant, C. F. (2013) Metabolome response to glucose in the β-cell line INS-1 832/13. J. Biol. Chem. 288, 10923-10935
11. MacDonald, M. J., Dobrzyn, A., Ntambi, J., and Stoker, S. W. (2008) The role of rapid lipogenesis in insulin secretion: insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells. Arch. Biochem. Biophys. 470, 153-162
12. MacDonald, M. J., Hasan, N. M., Dobrzyn, A., Stoker, S. W., Ntambi, J. M., Liu, X., and Sampath, H. (2013) Knockdown of pyruvate carboxylase or fatty acid synthase lowers numerous lipids and glucose-stimulated insulin release in insulinoma cells. Arch. Biochem. Biophys. 532, 23-31
13. Briaud, I., Harmon, J. S., Kelpe, C. L., Segu, V. B., and Poitout, V. (2001) Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50, 315-321
14. Prentki, M., and Madiraju, S. R. (2012) Glycerolipid/free fatty acid cycle and islet β-cell function in health, obesity and diabetes. Mol. Cell Endocrinol. 353, 88-100
15. Poitout, V., and Robertson, R. P. (2002) Minireview: secondary β-cell failure in type 2 diabetes: a convergence of glucotoxicity and lipotoxicity. Endocrinology 143, 339-342
16. Kruit, J. K., Wijesekara, N., Fox, J. E. M., Dai, X.-Q., Brunham, L. R., Searle, G. J., Morgan, G. P., Costin, A. J., Tang, R., Bhattacharjee, A., Johnson, J. D., Light, P. E., Marsh, B. J., Macdonald, P. E., Verchere, C. B., and Hayden, M. R. (2011) Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules. Diabetes 60, 3186-3196
17. Brunengraber, H., and Roe, C. R. (2006) Anaplerotic molecules: current and future. J. Inherit. Metab. Dis. 29, 327-331
18. Jensen, M. V., Joseph, J. W., Ronnebaum, S. M., Burgess, S. C., Sherry, A. D., and Newgard, C. B. (2008) Metabolic cycling in control of glucose-stimulated insulin secretion. Am. J. Physiol. Endocrinol. Metab. 295, E1287-E1297
19. Cline, G. W. (2011) Fuel-stimulated insulin secretion depends upon mitochondria activation and the integration of mitochondrial and cytosolic substrate cycles. Diabetes Metab. J. 35, 458-465
20. Cline, G. W., Pongratz, R. L., Zhao, X., and Papas, K. K. (2011) Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis. Biochem. Biophys. Res. Commun. 415, 30-35
21. Panten, U., Willenborg, M., Schumacher, K., Hamada, A., Ghaly, H., and Rustenbeck, I. (2013) Acute metabolic amplification of insulin secretion in mouse islets is mediated by mitochondrial export of metabolites, but not by mitochondrial energy generation. Metabolism 62, 1375-1386
22. MacDonald, M. J., Longacre, M. J., Warner, T. F., and Thonpho, A. (2013) High level of ATP citrate lyase expression in human and rat pancreatic islets. Horm. Metab. Res. 45, 391-393
23. Hasan, N. M., Longacre, M. J., Stoker, S. W., Boonsaen, T., Jitrapakdee, S., Kendrick, M. A., Wallace, J. C., and MacDonald, M. J. (2008) Impaired anaplerosis and insulin secretion in insulinoma cells caused by siRNA-mediated suppression of pyruvate carboxylase. J. Biol. Chem. 283, 28048-28059
24. Xu, J., Han, J., Long, Y. S., Epstein, P. N., and Liu, Y. Q. (2008) The role of pyruvate carboxylase in insulin secretion and proliferation in rat pancreatic beta cells. Diabetologia 51, 2022-2030
25. MacDonald, M. J., Longacre, M. J., Stoker, S. W., Brown, L. J., Hasan, N. M., and Kendrick, M. A. (2008) Acetoacetate and β-hydroxybutyrate in combination with other metabolites release insulin from INS-1 cells and provide clues about pathways in insulin secretion. Am. J. Physiol. Cell Physiol. 294, C442-C450
26. Macdonald, M. J., Hasan, N. M., and Longacre, M. J. (2008) Studies with leucine, β-hydroxybutyrate and ATP citrate lyase-deficient cells support the acetoacetate pathway of insulin secretion. Biochim. Biophys. Acta 1780, 966-972
27. MacDonald, M. J., Stoker, S. W., and Hasan, N. M. (2008) Anaplerosis from glucose, α-ketoisocaproate, and pyruvate in pancreatic islets, INS-1 cells and liver mitochondria. Mol. Cell Biochem. 313, 195-202
28. Hasan, N. M., Longacre, M. J., Seed Ahmed, M., Kendrick, M. A., Gu, H., Ostenson, C.-G., Fukao, T., and MacDonald, M. J. (2010) Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: knockdown of SCOT inhibits insulin release in rat insulinoma cells. Arch. Biochem. Biophys. 499, 62-68
29. MacDonald, M. J., Longacre, M. J., Stoker, S. W., Kendrick, M., Thonpho, A., Brown, L. J., Hasan, N. M., Jitrapakdee, S., Fukao, T., Hanson, M. S., Fernandez, L. A., and Odorico, J. (2011) Differences between human and rodent pancreatic islets: low pyruvate carboxylase, ATP citrate lyase and pyruvate carboxylation: high glucose-stimulated acetoacetate in human pancreatic islets. J. Biol. Chem. 286, 18383-18396
30. Sturek, J. M., Castle, J. D., Trace, A. P., Page, L. C., Castle, A. M., Evans-Molina, C., Parks, J. S., Mirmira, R. G., and Hedrick, C. C. (2010) An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells. J. Clin. Invest. 120, 2575-2589
31. Brun, T., Roche, E., Assimacopoulos-Jeannet, F., Corkey, B. E., Kim, K. H., and Prentki, M. (1996) Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. Diabetes 45, 190-198
32. Joseph, J. W., Odegaard, M. L., Ronnebaum, S. M., Burgess, S. C., Muehlbauer, J., Sherry, A. D., and Newgard, C. B. (2007) Normal flux through ATP-citrate lyase or fatty acid synthase is not required for glucose-stimulated insulin secretion. J. Biol. Chem. 282, 31592-31600
33. Mourad, N. I., Nenquin, M., and Henquin, J. C. (2010) Metabolic amplifying pathway increases both phases of insulin secretion independently of beta-cell actin microfilaments. Am. J. Physiol. Cell Physiol. 299, C389-C398
34. Straub, S. G., and Sharp, G. W. (2004) Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. Am. J. Physiol. Cell Physiol. 287, C565-C571
35. Brunham, L. R., Kruit, J. K., Pape, T. D., Timmins, J. M., Reuwer, A. Q., Vasanji, Z., Marsh, B. J., Rodrigues, B., Johnson, J. D., Parks, J. S., Verchere, C. B., and Hayden, M. R. (2007) β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat. Med. 13, 340-347
36. Hohmeier, H. E., Mulder, H., Chen, G., Henkel-Rieger, R., Prentki, M., and Newgard, C. B. (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49, 424-430
37. MacDonald, M. J., and Grewe, B. K. (1981) Inhibition of phosphoenolpyruvate carboxykinase, glyceroneogenesis and fatty acid synthesis in rat adipose tissue by quinolinate and 3-mercaptopicolinate. Biochim. Biophys. Acta 663, 302-313
38. Rana, R. S., Kowluru, A., and MacDonald, M. J. (1986) Secretagogue-responsive and -unresponsive pools of phosphatidylinositol in pancreatic islets. Arch. Biochem. Biophys. 245, 411-416
39. Rana, R. S., Kowluru, A., and MacDonald, M. J. (1986) Enzymes of phospholipid metabolism in rat pancreatic islets: subcellular distribution and the effect of glucose and calcium. J. Cell. Biochem. 32, 143-150
40. Kowluru, A., Rana, R. S., and MacDonald, M. J. (1985) Phospholipid methyltransferase activity in pancreatic islets: activation by calcium. Arch. Biochem. Biophys. 242, 72-81
41. Kowluru, A., Rabaglia, M. E., Muse, K. E., and Metz, S. A. (1994) Subcellular localization and kinetic characterization of guanine nucleotide binding proteins in normal rat and human pancreatic islets and transformed βcells. Biochim. Biophys. Acta 1222, 348-359
42. Wang, Z., and Thurmond, D. C. (2010) Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion. J. Biol. Chem. 285, 6186-6197
43. Spurlin, B. A., and Thurmond, D. C. (2006) Syntaxin 4 facilitates biphasic glucose-stimulated insulin secretion from pancreatic beta-cells. Mol. Endocrinol. 20, 183-193
44. Rhodes, C. J., Brennan, S. O., and Hutton, J. C. (1989) Proalbumin to albumin conversion by a proinsulin processing endopeptidase of insulin secretory granules. J. Biol. Chem. 264, 14240-14245
45. Bligh, E. G., and Dyer, W. J. (1959) A rapid method of total lipid extraction and purification. Can. J. Biol. Chem. 37, 911-917
46. Dobrzyn, A., Dobrzyn, P., Miyazaki, M., Sampath, H., Chu, K., and Ntambi, J. M. (2005) Stearoyl-CoA desaturase 1 deficiency increases CTP: choline cytidylyltransferase translocation into the membrane and enhances phosphatidylcholine synthesis in liver. J. Biol. Chem. 280, 23356-23362
47. MacDonald, M. J. (1981) High content of mitochondrial glycerol-3-phosphate dehydrogenase in pancreatic islets and its inhibition by diazoxide. J. Biol. Chem. 256, 8287-8290
48. Breckenridge, W. C., Gombos, G., and Morgan, I. G. (1972) The lipid composition of adult rat brain synaptosomal plasma membranes. Biochim. Biophys. Acta 266, 695-707
49. Breckenridge, W. C., Morgan, I. G., Zanetta, J. P., and Vincendon, G. (1973) Adult rat brain synaptic vesicles. II. Lipid composition. Biochim. Biophys. Acta 320, 681-686
50. Winkler, H. (1976) The composition of adrenal chromaffin granules: an assessment of controversial results. Neuroscience 1, 65-80
51. Dreyfus, H., Aunis, D., Harth, S., and Mandel, P. (1977) Gangliosides and phospholipids of the membranes from bovine adrenal medullary chromaffin granules. Biochim. Biophys. Acta 489, 89-97
52. Westhead, E. W. (1987) Lipid composition and orientation in secretory vesicles. Ann. N.Y. Acad. Sci. 493, 92-100
53. Castle, J. D., Cameron, R. S., Arvan, P., von Zastrow, M., and Rudnick, G. (1987) Similarities and differences among neuroendocrine, exocrine, and endocytic vesicles. Ann. N.Y. Acad. Sci. 493, 448-460
54. Thiele, C., and Huttner, W. B. (1998) Protein and lipid sorting from the trans-Golgi network to secretory granules: recent developments. Semin. Cell Dev. Biol. 9, 511-516
55. Vance, D. E., and Vance, J. E. (2008) in Biochemistry of Lipids, Lipoproteins and Membranes, 5th Ed. (Vance, D. E., and Vance, J. E., eds) pp. 213-244, Elsevier, Amsterdam
56. Vance, J. E., and Tasseva, G. (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim. Biophys. Acta 1831, 543-554
57. Rana, R. S., Mertz, R. J., Kowluru, A., Dixon, J. F., Hokin, L. E., and MacDonald, M. J. (1985) Evidence for glucose-responsive and -unresponsive pools of phospholipid in pancreatic islets. J. Biol. Chem. 260, 7861-7867
58. Rana, R. S., Sekar, M. C., Mertz, R. J., Hokins, L. E., and MacDonald, M. J. (1987) Potentiation by glucose metabolites of inositol trisphosphate-induced calcium mobilization in permeabilized rat pancreatic islets. J. Biol. Chem. 262, 13567-13570
59. Turk, J., Wolf, B. A., Lefkowith, J. B., Stump, W. T., and McDaniel, M. L. (1986) Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids. Biochim. Biophys. Acta 879, 399-409
60. Turk, J., Wolf, B. A., and McDaniel, M. L. (1986) Glucose-induced accumulation of inositol trisphosphates in isolated pancreatic islets. Predominance of the 1,3,4-isomer. Biochem. J. 237, 259-263
61. Kelley, G. G., Zawalich, K. C., and Zawalich, W. S. (1995) Synergistic interaction of glucose and neurohumoral agonists to stimulate islet phosphoinositide hydrolysis. Am. J. Physiol. 269, E575-E582
62. Zhang, Z., Hui, E., Chapman, E. R., and Jackson, M. B. (2009) Phosphatidylserine regulation of Ca2+-triggered exocytosis and fusion pores in PC12 cells. Mol. Biol. Cell 20, 5086-5095
63. Lam, A. D., Tryoen-Toth, P., Tsai, B., Vitale, N., and Stuenkel, E. L. (2008) SNARE-catalyzed fusion events are regulated by syntaxin 1A-lipid interactions. Mol. Biol. Cell 19, 485-497
64. Jackson, M. B., and Chapman, E. R. (2006) Fusion pores and fusion machines in Ca2+-triggered exocytosis. Annu. Rev. Biophys. Biomol. Struct. 35, 135-160
65. Chapman, E. R. (2008) How does synaptotagmin trigger neurotransmitter release? Annu. Rev. Biochem. 77, 615-641
66. Morton, L. A., Yang, H., Saludes, J. P., Fiorini, Z., Beninson, L., Chapman, E. R., Fleshner, M., Xue, D., and Yin, H. (2013) MARCKS-ED peptide as a curvature and lipid sensor. ACS Chem. Biol. 8, 218-225
67. Yeung, T., Gilbert, G. E., Shi, J., Silvius, J., Kapus, A., and Grinstein, S. (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319, 210-213
68. Williams, D., Vicôgne, J., Zaitseva, I., McLaughlin, S., and Pessin, J. E. (2009) Evidence that electrostatic interactions between vesicle-associated membrane protein 2 and acidic phospholipids may modulate the fusion of transport vesicles with the plasma membrane. Mol. Biol. Cell 20, 4910-4919
69. Ramanadham, S., Bohrer, A., Gross, R. W., and Turk, J. (1993) Mass spectrometric characterization of arachidonate-containing plasmalogens in human pancreatic islets and in rat islet beta-cells and subcellular membranes. Biochemistry 32, 13499-13509
70. Ramanadham, S., Hsu, F. F., Bohrer, A., Nowatzke, W., Ma, Z., and Turk, J. (1998) Electrospray ionization mass spectrometric analyses of phospholipids from rat and human pancreatic islets and subcellular membranes: comparison to other tissues and implications for membrane fusion in insulin exocytosis. Biochemistry 37, 4553-4567
71. Wang, T., Smith, E. A., Chapman, E. R., and Weisshaar, J. C. (2009) Lipid mixing and content release in single-vesicle, SNARE-driven fusion assay with 1-5 ms resolution. Biophys. J. 96, 4122-4131
72. de Haro, L., Ferracci, G., Opi, S., Iborra, C., Quetglas, S., Miquelis, R., Lévêque, and Seagar, M. (2004) Ca2+/calmodulin transfers the membrane- proximal lipid-binding domain of the v-SNARE synaptobrevin from cis to trans bilayers. Proc. Natl. Acad. Sci. U.S.A. 101, 1578-1583
73. Söllner, T., Whiteheart, S. W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P., and Rothman, J. E. (1993) SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318-324
74. Domanska, M. K., Kiessling, V., and Tamm, L. K. (2010) Docking and fast fusion of synaptobrevin vesicles depends on the lipid compositions of the vesicle and the acceptor SNARE complex-containing target membrane. Biophys. J. 99, 2936-2946
75. Quetglas, S., Iborra, C., Sasakawa, N., De Haro, L., Kumakura, K., Sato, K., Leveque, C., and Seagar, M. (2002) Calmodulin and lipid binding to synaptobrevin regulates calcium-dependent exocytosis. EMBO J. 21, 3970-3979
76. Kooijman, E. E., King, K. E., Gangoda, M., and Gericke, A. (2009) Ionization properties of phosphatidylinositol polyphosphates in mixed model membranes. Biochemistry 48, 9360-9371
77. Wheeler, M. B., Sheu, L., Ghai, M., Bouquillon, A., Grondin, G., Weller, U., Beaudoin, A. R., Bennett, M. K., Trimble, W. S., and Gaisano, H. Y. (1996) Characterization of SNARE protein expression in beta cell lines and pancreatic islets. Endocrinology 137, 1340-1348
78. Thurmond, D. C. (2000) Regulation of insulin action and insulin secretion by SNARE-mediated vesicle exocytosis. in Madame Curie Bioscience Database, Landes Bioscience, Austin, TX
79. Thurmond, D. C., Gonelle-Gispert, C., Furukawa, M., Halban, P. A., and Pessin, J. E. (2003) Glucose-stimulated insulin secretion is coupled to the interaction of actin with the t-SNARE (target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein) complex. Mol. Endocrinol. 17, 732-742
80. Oh, E., Kalwat, M. A., Kim, M. J., Verhage, M., and Thurmond, D. C. (2012) Munc18-1 regulates first-phase insulin release by promoting granule docking to multiple syntaxin isoforms. J. Biol. Chem. 287, 25821-25833
81. Wang, Z., and Thurmond, D. C. (2009) Mechanisms of biphasic insulin-granule exocytosis: roles of the cytoskeleton, small GTPases and SNARE proteins. J. Cell Sci. 122, 893-903
82. Daniel, S., Noda, M., Straub, S. G., and Sharp, G. W. (1999) Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 48, 1686-1690
83. Jacobsson, G., Bean, A. J., Scheller, R. H., Juntti-Berggren, L., Deeney, J. T., Berggren, P. O., and Meister, B. (1994) Identification of synaptic proteins and their isoform mRNAs in compartments of pancreatic endocrine cells. Proc. Natl. Acad. Sci. U.S.A. 91, 12487-12491
84. Daleke, D. L. (2007) Phospholipid flippases. J. Biol. Chem. 282, 821-825
85. Clark, M. R. (2011) Flippin' lipids. Nat. Immunol. 12, 373-375
86. Devaux, P. F., Herrmann, A., Ohlwein, N., and Kozlov, M. M. (2008) How lipid flippases can modulate membrane structure. Biochim. Biophys. Acta 1778, 1591-1600
87. van der Mark, V. A., Elferink, R. P., and Paulusma, C. C. (2013) P4 ATPases: flippases in health and disease. Int. J. Mol. Sci. 14, 7897-7922