Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila.
The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemia-related heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and lipid-induced cardiomyopathy. In the present study, we report that the Drosophila easily shocked (eas) mutants that harbor a disturbance in phosphatidylethanolamine (PE) synthesis display tachycardia and defects in cardiac relaxation and are prone to developing cardiac arrest and fibrillation under stress. The eas mutant hearts exhibit elevated concentrations of triglycerides, suggestive of a metabolic, diabetic-like heart phenotype. Moreover, the low PE levels in eas flies mimic the effects of cholesterol deficiency in vertebrates by stimulating the Drosophila sterol regulatory element-binding protein (dSREBP) pathway. Significantly, cardiac-specific elevation of dSREBP signaling adversely affects heart function, reflecting the cardiac eas phenotype, whereas suppressing dSREBP or lipogenic target gene function in eas hearts rescues the cardiac hyperlipidemia and heart function disorders. These findings suggest that dysregulated phospholipid signaling that alters SREBP activity contributes to the progression of impaired heart function in flies and identifies a potential link to lipotoxic cardiac diseases in humans.
Development and Aging Program, NASCR (Neuroscience, Aging, and Stem Cell Research) Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Hui-Ying
HY
Lim
Weidong
W
Wang
Robert J
RJ
Wessells
Karen
K
Ocorr
Rolf
R
Bodmer
D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006321:Heart / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism*; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
D029721:Drosophila Proteins; D010743:Phospholipids; D051779:Sterol Regulatory Element Binding Proteins
J Biol Chem. 2001 Oct 12;276(41):38061-7
11500520
J Clin Invest. 2003 Feb;111(3):419-26
12569168
Physiol Rev. 2008 Apr;88(2):389-419
18391168
J Biol Chem. 2009 Sep 18;284(38):25704-13
19625253
J Cell Physiol. 1988 Oct;137(1):1-13
3170651
Science. 2002 May 3;296(5569):857-8
11988558
J Vis Exp. 2009 Sep 16;(31):
19759521
Clin Sci (Lond). 2008 Feb;114(3):195-210
18184113
Cell. 2010 Apr 2;141(1):142-53
20371351
Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E25-32
10893319
J Lipid Res. 2009 Nov;50(11):2137-8
19687505
Hypertension. 2008 Aug;52(2):181-7
18574077
Trends Cardiovasc Med. 2007 Jul;17(5):177-82
17574126
FEBS J. 2009 Feb;276(3):616-21
19143830
Cell Metab. 2010 Nov 3;12(5):533-44
21035763
Cell. 1994 Oct 7;79(1):23-33
7923374
Dev Biol. 2008 Jun 1;318(1):29-37
18430414
Aging Cell. 2009 Sep;8(5):542-52
19594484
Circ Res. 2005 Feb 4;96(2):225-33
15618539
World J Gastroenterol. 2009 Apr 14;15(14):1751-8
19360919
Endocrinology. 2003 Aug;144(8):3483-90
12865329
Subcell Biochem. 2008;49:299-324
18751916
J Biol Chem. 1998 Jun 26;273(26):16112-21
9632664
Am J Physiol. 1995 Feb;268(2 Pt 2):H773-80
7864204
Mech Dev. 2001 Nov;109(1):51-9
11677052
Biochemistry. 2005 Apr 5;44(13):5234-45
15794660
Biotechniques. 2009 Feb;46(2):101-13
19317655
Dev Cell. 2002 Feb;2(2):229-38
11832248
J Biol Chem. 1992 Jul 25;267(21):14586-91
1634506
Mol Cell Biochem. 1997 Oct;175(1-2):153-62
9350047
J Pharmacol Exp Ther. 2003 Mar;304(3):1003-9
12604675
Nat Genet. 2004 Dec;36(12):1275-81
15565107
J Lipid Res. 2008 Jul;49(7):1377-87
18204094
J Cell Biol. 1989 Nov;109(5):2157-67
2509482
Cell Metab. 2007 Oct;6(4):257-66
17908555
J Clin Invest. 2001 Apr;107(7):813-22
11285300
J Mol Cell Cardiol. 2000 Jun;32(6):1061-74
10888258
Lipids. 1966 May;1(3):209-15
17805613
Genes Dev. 2009 Nov 15;23(22):2578-91
19933148
PLoS One. 2007 Jul 11;2(7):e601
17622346
Biochim Biophys Acta. 2002 Dec 30;1585(2-3):202-12
12531555
J Biol Chem. 2009 Oct 2;284(40):27077-89
19666474
Science. 2002 May 3;296(5569):879-83
11988566
Circ Res. 2007 Sep 14;101(6):545-59
17872473
Am J Cardiol. 1998 Sep 3;82(5A):18K-24K
9737482
Cell Metab. 2006 Jun;3(6):439-48
16753579
Dev Biol. 2005 Apr 1;280(1):177-86
15766757
Cell Metab. 2008 Sep;8(3):224-36
18762023
Development. 2006 Mar;133(6):1175-82
16467358
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1195-9
8577739
Genetics. 2010 May;185(1):189-98
20176975
Biotechniques. 2004 Jul;37(1):58-60, 62, 64 passim
15283201
Biochem Genet. 2001 Oct;39(9-10):339-49
11758729
J Neurobiol. 2000 Jan;42(1):33-48
10623899
J Lipid Res. 2004 Aug;45(8):1500-9
15175356
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3943-8
17360457
J Clin Invest. 2007 Oct;117(10):2791-801
17823655
Annu Rev Biochem. 1957;26:119-48
13488391