Letting lipids go: Hormone-sensitive lipase

Current Opinion in Lipidology

Volumn 14, Issue 3, 2003, Pages 289-297

  Haemmerle, Guenter ^a   Zimmermann, Robert ^a   Zechner, Rudolf ^a  

^a UNIVERSITY OF GRAZ   (Austria)

Author keywords

Diabetes; Energy metabolism; Hormone sensitive lipase; Obesity

Indexed keywords

CHOLESTEROL ESTER; FATTY ACID DERIVATIVE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPID; STEROID HORMONE; TRIACYLGLYCEROL; TRIACYLGLYCEROL LIPASE;

ADIPOSE TISSUE; ADRENAL GLAND; CATABOLISM; ENZYME ACTIVITY; ENZYME DEFICIENCY; ENZYME DEGRADATION; ENZYME INHIBITION; HORMONE SENSITIVITY; HUMAN; HYDROLYSIS; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; TESTIS FUNCTION;

ADIPOSE TISSUE; ADRENAL GLANDS; ANIMALS; ARTERIOSCLEROSIS; CARBOHYDRATE METABOLISM; CHOLESTEROL ESTERASE; CHOLESTEROL ESTERS; DIABETES MELLITUS, TYPE 2; FATTY ACIDS; HUMANS; LIPID METABOLISM; MALE; OBESITY; TESTIS;

ANIMALIA;

EID: 0038509024     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-200306000-00009     Document Type: Review

References (112)

1. Kelner K, Helmuth L. Obesity: what is to be done? Science 2003; 299:845.
2. Spiegelman Bruce M, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104;531-543.
3. Kraemer FB, Shen WJ. Hormone-sensitive lipase:control of intracellular tri(di)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res 2002; 43:1585-1594. An excellent recent review about the regulation and function of HSL.
4. Holm C, Kirchgessner TG, Svenson KL, et al. Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3. Science 1988; 241:1503-1506.
5. Kraemer FB, Patel S, Singh Bist A, et al. Detection of hormone-sensitive lipase in various tissues: II. Regulation in the rat testis by human chorionic gonadotropin. J Lipid Res 1993; 34:609-616.
6. Langfort J, Ploug T, Ihlemann J, et al. Hormone-sensitive lipase (HSL) expression and regulation in skeletal muscle. Adv Exp Med Biol 1998; 441:219-228.
7. Contreras JA, Holm C, Martin A, et al. Presence of hormone-sensitive lipase mRNA in J774 macrophages. Isr J Med Sci 1994; 30:778-781.
8. Holm C, Belfrage P, Fredrikson G. Immunological evidence for the presence of hormone-sensitive lipase in rat tissues other than adipose tissue. Biochem Biophys Res Commun 1987; 148:99-105.
9. Khoo JC, Reue K, Steinberg D, Schotz MC. Expression of hormone-sensitive lipase mRNA in macrophages. J Lipid Res 1993; 34:1969-1974.
10. Langin D, Laurell H, Holst LS, et al. Gene organization and primary structure of human hormone-sensitive lipase: possible significance of a sequence homology with a lipase of Moraxella TA144, an Antarctic bacterium. Proc Natl Acad Sci U S A 1993; 90:4897-4901.
11. Grober J, Laurell H, Blaise R, et al. Characterization of the promoter of human adipocyte hormone-sensitive lipase. Biochem J 1997; 328:453-461.
12. Laurin NN, Wang SP, Mitchell GA. The hormone-sensitive lipase gene is transcribed from at least five alternative first exons in mouse adipose tissue. Mamm Genome 2000; 11:972-978.
13. Holst LS, Langin D, Mulder H, et al. Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase. Genomics 1996; 35:441-447.
14. Mairal A, Melaine N, Laurell H, et al. Characterization of a novel testicular form of human hormone-sensitive lipase. Biochem Biophys Res Commun 2002; 291:286-290. The authors identified a 3.3 kb HSL mRNA possessing a 5′ end from a novel testis-specific exon.
15. Shen WJ, Patel S, Hong R, Kraemer FB. Hormone-sensitive lipase functions as an oligomer. Biochemistry 2000; 39:2392-2398.
16. Belfrage P, Jergil B, Stralfors P, Tornqvist H. Hormone-sensitive lipase of rat adipose tissue: identification and some properties of the enzyme protein. FEBS Lett 1977; 75:259-264.
17. Yeaman SJ. Hormone-sensitive lipase: a multipurpose enzyme in lipid metabolism. Biochim Biophys Acta 1990; 1052:128-132.
18. Wei S, Lai K, Patel S, et al. Retinyl ester hydrolysis and retinol efflux from BFC-1beta adipocytes. J Biol Chem 1997; 272:14159-14165.
19. Fredrikson G, Tornqvist H, Belfrage P. Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochim Biophys Acta 1986; 876:288-293.
20. Fredrikson G, Stralfors P, Nilsson NO, Belfrage P. Hormone-sensitive lipase of rat adipose tissue: purification and some properties. J Biol Chem 1981; 256:6311-6320.
21. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem 2002; 277:4806-4815. This study shows that HSL is the rate-limiting enzyme for the cellular catabolism of DG in adipose tissue and muscle and provides evidence for the presence of an additional lipase activated by β-adrenergic stimulation.
22. Raclot T. Selective mobilization of fatty acids from white fat cells: evidence for a relationship to the polarity of triacylglycerols. Biochem J 1997; 322:483-489.
23. Raclot T, Holm C, Langin D. A role for hormone-sensitive lipase in the selective mobilization of adipose tissue fatty acids. Biochim Biophys Acta 2001; 1532:88-96.
24. Holm C, Osterlund T, Laurell H, Contreras JA. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu Rev Nutr 2000; 20:365-393.
25. Londos C, Brasaemle DL, Schultz CJ, et al. On the control of lipolysis in adipocytes. Ann N Y Acad Sci 1999; 892:155-168.
26. Yip RG, Goodman HM. Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi alpha2 to lower density membrane fractions. Endocrinology 1999; 140:1219-1227.
27. Shepherd RE, Noble EG, Klug GA, Gollnick PD. Lipolysis and cAMP accumulation in adipocytes in response to physical training. J Appl Physiol 1981; 50:143-148.
28. Greenberg AS, Shen WJ, Muliro K, et al. Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway. J Biol Chem 2001; 276:45456-45461.
29. Brasaemle DL, Levin DM, Adler Wailes DC, Londos C. The lipolytic stimulation of 3T3-L1 adipocytes promotes the translocation of hormone-sensitive lipase to the surfaces of lipid storage droplets. Biochim Biophys Acta 2000; 1483:251-262.
30. Clifford GM, McCormick DK, Vernon RG, Yeaman SJ. Translocation of perilipin and hormone-sensitive lipase in response to lipolytic hormones. Biochem Soc Trans 1997; 25:672-678.
31. Clifford GM, Londos C, Kraemer FB, et al. Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. J Biol Chem 2000; 275:5011-5015.
32. Syu LJ, Saltiel AR. Lipotransin: a novel docking protein for hormone-sensitive lipase. Mol Cell 1999; 4:109-115.
33. Souza SC, Muliro KV, Liscum L, et al. Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. J Biol Chem 2002; 277:8267-8272. A study which demonstrates that perilipin expression and phosphorylation state are critical regulators of storage and hydrolysis of lipids.
34. Londos C, Gruia Gray J, Brasaemle DL, et al. Perilipin: possible roles in structure and metabolism of intracellular neutral lipids in adipocytes and steroidogenic cells. Int J Obes Relat Metab Disord 1996; 20:97-101.
35. Shen WJ, Sridhar K, Bernlohr DA, Kraemer FB. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proc Natl Acad Sci U S A 1999; 96:5528-5532.
36. Shen WJ, Liang Y, Hong R, et al. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase. J Biol Chem 2001; 276:49443-49448.
37. Cummings DE, Brandon EP, Planas JV, et al. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 1996; 382:622-626.
38. Martinez Botas J, Anderson JB, Tessier D, et al. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet 2000; 26:474-479.
39. Tansey JT, Sztalryd C, Gruia Gray J, et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci U S A 2001; 98:6494-6499.
40. Coe NR, Simpson MA, Bernlohr DA. Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. J Lipid Res 1999; 40:967-972.
41. Large V, Arner P, Reynisdottir S, et al. Hormone-sensitive lipase expression and activity in relation to lipolysis in human fat cells. J Lipid Res 1998; 39:1688-1695.
42. Sztalryd C, Komaromy MC, Kraemer FB. Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest 1995; 95:2652-2661.
43. Osuga J, Ishibashi S, Oka T, et al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci U S A 2000; 97:787-792.
44. Okazaki H, Osuga J, Tamura Y, et al. Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases. Diabetes 2002; 51:3368-3375. This study demonstrates that lipolysis is mediated not only by HSL but also by a non-HSL TG lipase, which responses to lipolytic hormones are similar to those of HSL.
45. Lehner R, Vance DE. Cloning and expression of a cDNA encoding a hepatic microsomal lipase that mobilizes stored triacylglycerol. Biochem J 1999; 343:1-10.
46. Liu WS, Heckman CA. The sevenfold way of PKC regulation. Cell Signal 1998; 10:529-542.
47. Pettitt TR, Wakelam MJ. Diacylglycerol kinase epsilon, but not zeta, selectively removes polyunsaturated diacylglycerol, inducing altered protein kinase C distribution in vivo. J Biol Chem 1999; 274:36181-36186.
48. Ron D, Kazanietz MG. New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB J 1999; 13:1658-1676.
49. Wang SP, Laurin N, Himms Hagen J, et al. The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes Res 2001; 9:119-128. HSL-deficient mice have normal body weight but reduced abdominal fat mass compared with normal littermates.
50. Kalderon B, Mayorek N, Berry E, et al. Fatty acid cycling in the fasting rat. Am J Physiol Endocrinol Metab 2000; 279:E221-E227.
51. Chen HC, Stone SJ, Zhou P, et al. Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue. Diabetes 2002; 51:3189-3195.
52. Smith SJ, Cases S, Jensen DR, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 2000; 25:87-90.
53. Lucas S, Tavernier G, Tiraby C, et al. Expression of human hormone-sensitive lipase in white adipose tissue of transgenic mice increases lipase activity but does not enhance in vitro lipolysis. J Lipid Res 2003; 44:154-163. The data show that 3-fold overexpression of human HSL, despite increased lipase activity, does not lead to enhanced lipolysis.
54. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res 1999; 40:2059-2066.
55. Klannemark M, Orho M, Langin D, et al. The putative role of the hormone-sensitive lipase gene in the pathogenesis of type II diabetes mellitus and abdominal obesity. Diabetologia 1998; 41:1516-1522.
56. Lofgren P, Hoffstedt J, Ryden M, et al. Major gender differences in the lipolytic capacity of abdominal subcutaneous fat cells in obesity observed before and after long-term weight reduction. J Clin Endocrinol Metab 2002; 87:764-771.
57. Elizalde M, Ryden M, van Harmelen V, et al. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans. J Lipid Res 2000; 41:1244-1251.
58. Magre J, Laurell H, Fizames C, et al. Human hormone-sensitive lipase: genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM. Diabetes 1998; 47:284-286.
59. Hoffstedt J, Arner P, Schalling M, et al. A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function. Diabetes 2001; 50:2410-2413.
60. Clement K, Dina C, Basdevant A, et al. A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. Diabetes 1999; 48:398-402.
61. Talmud PJ, Palmen J, Walker M. Identification of genetic variation in the human hormone-sensitive lipase gene and 5′ sequences: homology of 5′ sequences with mouse promoter and identification of potential regulatory elements. Biochem Biophys Res Commun 1998; 252:661-668.
62. Garenc C, Perusse L, Chagnon YC, et al. The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study. Int J Obes Relat Metab Disord 2002; 26:220-227. This study suggests that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race- and insulin-dependent.
63. Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart. Annu Rev Physiol 1974; 36:413-459.
64. Haemmerle G, Zimmermann R, Strauss JG, et al. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem 2002; 277:12946-12952. The study demonstrates that HSL deficiency affects the metabolism of lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue.
65. Suzuki J, Shen WJ, Nelson BD, et al. Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression. Am J Physiol Endocrinol Metab 2001; 281:E857-E866.
66. Tavintharan S, Kashyap ML. The benefits of niacin in atherosclerosis. Curr Atheroscler Rep 2001; 3:74-82.
67. Aktories K, Schultz G, Jakobs KH. Inhibition of adenylate cyclase and stimulation of a high affinity GTPase by the antilipolytic agents, nicotinic acid, acipimox and various related compounds. Arzneimittelforschung 1983; 33:1525-1527.
68. Aktories K, Schultz G, Jakobs KH. Islet-activating protein prevents nicotinic acid-induced GTPase stimulation and GTP but not GTP gamma S-induced adenylate cyclase inhibition in rat adipocytes. FEBS Lett 1983; 156:88-92.
69. Green A, Milligan G, Dobias SB. Gi down-regulation as a mechanism for heterologous desensitization in adipocytes. J Biol Chem 1992; 267:3223-3299.
70. Wise A, Foord SM, Fraser N J, et al. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 2003; 278:9869-9874.
71. Brown MS, Ho YK, Goldstein JL. The cholesteryl ester cycle in macrophage foam cells: continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. J Biol Chem 1980; 255:9344-9352.
72. Krause DR, Hartman AD. Adipose tissue and cholesterol metabolism. J Lipid Res 1984; 25:97-110.
73. Escary JL, Choy HA, Reue K, Schotz MC. Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells. Arterioscler Thromb Vasc Biol 1998; 18:991-998.
74. Okazaki H, Osuga J, Tsukamoto K, et al. Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase. J Biol Chem 2002; 277:31893-31899. The authors demonstrate that increased hydrolysis of CE by the overexpression of HSL leads to complete elimination of CE from THP-1 foam cells net only by increasing efflux but also by decreasing influx of cholesterol.
75. Escary JL, Choy HA, Reue K, et al. Paradoxical effect on atheresclerosis of hormone-sensitive lipase overexpression in macrophages. J Lipid Res 1999; 40:397-404.
76. Contreras JA. Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages. Biochem Biophys Res Commun 2002; 292:900-903. Macrophages from HSL null mice hydrolyze cytosolic stores of cholesteryl esters at a comparable rate to that of peritoneal macrophages from wild-type mice.
77. Li H, Brochu M, Wang SP, et al. Hormone-sensitive lipase deficiency in mice causes lipid storage in the adrenal cortex and impaired corticosterone response to corticotropin stimulation. Endocrinology 2002; 143:3333-3340. The authors demonstrate that HSL is functional in brain and that HSL deficiency results in a marked accumulation of lipid droplets both in zona glomerulosa and zona fasciculata.
78. Kraemer FB, Shen WJ, Natu V, et al. Adrenal neutral cholesteryl ester hydrolase: identification, subcellular distribution, and sex differences. Endocrinology 2002; 143:801-806. The study identifies HSL as the major CE hydrolase in adrenals.
79. Chung S, Wang SP, Pan L, et al. Infertility and testicular defects in hormone-sensitive lipase-deficient mice. Endocrinology 2001; 142:4272-4281.
80. Gupta RS, Dixit VP. Effect of dietary cholesterol on spermatogenesis. Z Ernahrungswiss 1988; 27:236-243.
81. Livera G, Rouiller Fabre V, Durand P, Habert R. Multiple effects of retinoids on the development of Sertoli, germ, and Leydig cells of fetal and neonatal rat testis in culture. Biol Reprod 2000; 62:1303-1314.
82. Lufkin T, Lohnes D, Mark M, et al. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A 1993; 90:7225-7229.
83. Kastner P, Mark M, Leid M, et al. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev 1996; 10:80-92.
84. Grober J, Lucas S, Soredhe-Winzell M, et al. Hormone-sensitive lipase is a cholesterol esterase of the intestinal mucosa. J Biol Chem 2003; 278:6510-6515 The work demonstrates that HSL is expressed in the mucosa of the small intestine and participates in acylglycerol hydrolysis in jejunal enterocytes and cholesteryl ester hydrolysis throughout the small intestine.
85. Buhman KK, Accad M, Novak S, et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000; 6:1341-1347.
86. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46:3-10.
87. McGarry JD. Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2001; 51:7-18.
88. Frayn KN, Coppack SW, Fielding BA, Humphreys SM. Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization. Adv Enzyme Regul 1995; 35:163-178.
89. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur J Clin Invest 2002; 32:14-23.
90. Magnusson I, Rothman DL, Katz LD, et al. Increased rate of gluconeogenesis in type II diabetes mellitus: a 13C nuclear magnetic resonance study. J Clin Invest 1992; 90:1323-1327.
91. Gupta G, Cases JA, She L, et al. Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation. Am J Physiol Endocrinol Metab 2000; 278:E985-E991.
92. Kim JK, Gavrilova O, Chen Y, et al. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000; 275:8456-8460.
93. Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest 1999; 103:365-372.
94. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 1995; 44:863-870.
95. McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia 1999; 42:128-138.
96. Zhou YP, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 1994; 93:870-876.
97. Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 1995; 44:1239-1242.
98. Reynisdottir S, Angelin B, Langin D, et al. Adipose tissue lipoprotein lipase and hormone-sensitive lipase: contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler Thromb Vasc Biol 1997; 17:2287-2292.
99. Reynisdottir S, Ellerfeldt K, Wahrenberg H, et al. Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. J Clin Invest 1994; 93:2590-2599.
100. Pihlajamaki J, Valve R, Karjalainen L, et al. The hormone sensitive lipase gene in familial combined hypertipidemia and insulin resistance. Eur J Clin Invest 2001; 31:302-308.
101. Stumvoll M, Wahl HG, Jacob S, et al. Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal. J Lipid Res 2001; 42:1782-1788.
102. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001; 98:7522-7527.
103. Roduit R, Masiello P, Wang SP, et al. A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. Diabetes 2001; 50:1970-1975. The results demonstrate an important role of HSL and endogenous beta-cell lipolysis in the coupling mechanism of glucose-stimulated insulin secretion and provide direct support for the concept that some lipid molecule(s), such as FFAs, fatty acyl-CoA or their derivatives, are implicated in beta-cell glucose signaling.
104. Mulder H, Holst LS, Svensson H, et al. Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells. Diabetes 1999; 48:228-232.
105. Winzell MS, Svensson H, Arner P, et al. The expression of hormone-sensitive lipase in clonal beta-cells and rat islets is induced by long-term exposure to high glucose. Diabetes 2001; 50:2225-2230. The study suggests that HSL is involved in the beta-cell responses to hyperglycemia and also in generating the lipid signal that is needed in stimulus-secretion coupling.
106. Briaud I, Harmon JS, Kelpe CL, et al. Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 2001; 50:315-321.
107. Kelpe CL, Johnson LM, Poitout V. Increasing triglyceride synthesis inhibits glucose-induced insulin secretion in isolated rat islets of Langerhans: a study using adenoviral expression of diacylglycerol acyltransferase. Endocrinology 2002; 143:3326-3332.
108. Prentki M, Matschinsky FM. Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 1987; 67:1185-1248.
109. Prentki M. New insights into pancreatic beta-cell metabolic signaling in insulin secretion. Eur J Endocrinol 1996; 134:272-286.
110. Yaney GC, Fairbanks JM, Deeney JT, et al. Potentiation of insulin secretion by phorbol esters is mediated by PKC-alpha and nPKC isoforms. Am J Physiol Endocrinol Metab 2002; 283:E880-E888.
111. Tian YM, Urquidi V, Ashcroft SJ. Protein kinase C in beta-cells: expression of multiple isoforms and involvement in cholinergic stimulation of insulin secretion. Mol Cell Endocrinol 1996; 119:185-193.
112. Peter Riesch B, Fathi M, Schlegel W, Wollheim CB. Glucose and carbachol generate 1,2-diacylglycerols by different mechanisms in pancreatic islets. J Clin Invest 1988; 81:1154-1161.