Sterol and diacylglycerol acyltransferase deficiency triggers fatty acid-mediated cell death.
Deletion of the acyltransferases responsible for triglyceride and steryl ester synthesis in Saccharomyces cerevisiae serves as a genetic model of diseases where lipid overload is a component. The yeast mutants lack detectable neutral lipids and cytoplasmic lipid droplets and are strikingly sensitive to unsaturated fatty acids. Expression of human diacylglycerol acyltransferase 2 in the yeast mutants was sufficient to reverse these phenotypes. Similar to mammalian cells, fatty acid-mediated death in yeast is apoptotic and presaged by transcriptional induction of stress-response pathways, elevated oxidative stress, and activation of the unfolded protein response. To identify pathways that protect cells from lipid excess, we performed genetic interaction and transcriptional profiling screens with the yeast acyltransferase mutants. We thus identified diacylglycerol kinase-mediated phosphatidic acid biosynthesis and production of phosphatidylcholine via methylation of phosphatidylethanolamine as modifiers of lipotoxicity. Accordingly, the combined ablation of phospholipid and triglyceride biosynthesis increased sensitivity to saturated fatty acids. Similarly, normal sphingolipid biosynthesis and vesicular transport were required for optimal growth upon denudation of triglyceride biosynthesis and also mediated resistance to exogenous fatty acids. In metazoans, many of these processes are implicated in insulin secretion thus linking lipotoxicity with early aspects of pancreatic beta-cell dysfunction, diabetes, and the metabolic syndrome.
Garbarino
Jeanne
J
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
Padamsee
Mahajabeen
M
Wilcox
Lisa
L
Oelkers
Peter M
PM
D'Ambrosio
Diana
D
Ruggles
Kelly V
KV
Ramsey
Nicole
N
Jabado
Omar
O
Turkish
Aaron
A
Sturley
Stephen L
SL
D016923:Cell Death / Q000187:drug effects; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism / Q000633:toxicity*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D050296:Microbial Viability; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013261:Sterols / Q000378:metabolism*
D005227:Fatty Acids; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C494880:DGA1 protein, S cerevisiae; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
J Biol Chem. 1989 Oct 5;264(28):16537-44
2674136
Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):110-6
19202381
Apoptosis. 2006 Jul;11(7):1111-9
16699958
J Biol Chem. 1995 Dec 15;270(50):29766-72
8530368
Cell. 2007 Mar 23;128(6):1147-59
17382883
Biochem Soc Trans. 2005 Nov;33(Pt 5):1182-5
16246077
Appl Environ Microbiol. 1997 Jul;63(7):2897-905
9212436
Cell. 2005 Nov 4;123(3):507-19
16269340
Biochim Biophys Acta. 2000 Sep 18;1469(2):101-20
10998572
J Clin Invest. 1996 Jun 15;97(12):2859-65
8675698
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3077-82
12629214
J Biol Chem. 2001 May 4;276(18):14890-5
11278654
Methods Mol Biol. 1993;19:153-67
7693219
J Biol Chem. 2008 Jul 18;283(29):20443-53
18458076
Bioinformatics. 2006 Apr 1;22(7):897-9
16455752
Science. 1996 May 31;272(5266):1353-6
8650549
J Cell Biol. 1999 May 17;145(4):757-67
10330404
Clin Nutr. 2004 Aug;23(4):721-32
15297111
Nucleic Acids Res. 2003 Feb 15;31(4):e15
12582260
J Bacteriol. 1973 Jun;114(3):1158-63
4576400
J Bacteriol. 1969 Oct;100(1):180-6
5344095
Clin Sci (Lond). 2005 Mar;108(3):245-53
15563273
J Biol Chem. 2008 Jul 18;283(29):20433-42
18458075
Can J Microbiol. 1976 Dec;22(12):1710-5
1009501
J Lipid Res. 1994 Oct;35(10):1850-60
7852862
J Lipid Res. 1996 Nov;37(11):2341-50
8978486
Biochem Soc Trans. 2000 Dec;28(6):700-2
11171176
Arch Microbiol. 1995 Dec;164(6):420-7
8588744
Am J Physiol Gastrointest Liver Physiol. 2007 Apr;292(4):G953-7
17095752
J Biol Chem. 2000 Mar 17;275(11):7597-603
10713067
J Bacteriol. 2002 Jan;184(2):519-24
11751830
Bioinformatics. 2004 Dec 12;20(18):3705-6
15297296
J Biol Chem. 2002 Mar 15;277(11):8877-81
11751875
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6027-32
11371634
Nat Cell Biol. 2003 Sep;5(9):781-92
12907943
Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1465-8
17194897
J Biol Chem. 2002 Feb 22;277(8):6478-82
11741946
J Biol Chem. 2005 Apr 15;280(15):14755-64
15671038
J Biol Chem. 1996 Jun 7;271(23):13293-6
8663192
Cell. 2007 Feb 9;128(3):577-87
17289575
Stat Appl Genet Mol Biol. 2003;2:Article1
16646779
J Biol Chem. 2004 Jul 23;279(30):31190-6
15155725
Diabetes. 2002 Jan;51(1):7-18
11756317
J Nutr. 2006 Dec;136(12):3005-9
17116711
Biochim Biophys Acta. 2003 Jul 4;1633(1):68-74
12842197
FEMS Microbiol Rev. 2003 Jun;27(2-3):215-37
12829269
Proc Natl Acad Sci U S A. 1981 Oct;78(10):6354-8
6273866
J Biol Chem. 1998 Oct 9;273(41):26765-71
9756920
J Biol Chem. 2000 May 26;275(21):15609-12
10747858
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W592-5
15980543
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502
9482914
J Biol Chem. 2009 Nov 6;284(45):30981-93
19608739
Curr Opin Cell Biol. 2001 Jun;13(3):349-55
11343907
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6487-92
10829075
J Biol Chem. 2003 Nov 21;278(47):47145-55
12963726
Cell Metab. 2007 Mar;5(3):167-79
17339025
Methods. 2001 Dec;25(4):402-8
11846609
J Biol Chem. 2001 Feb 9;276(6):4365-72
11085986
J Biol Chem. 2002 Sep 6;277(36):32466-72
12077145
Stat Appl Genet Mol Biol. 2004;3:Article3
16646809
J Pharmacol Exp Ther. 2006 Sep;318(3):1203-10
16757537
Biochim Biophys Acta. 1991 Nov 11;1090(3):326-32
1954254
J Cell Biol. 1997 Nov 3;139(3):729-34
9348289