Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome.
Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in ω-3 and ω-6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.
From the Integrated Physiology Graduate Program.|Division of Reproductive Sciences, and.
Andrew E
AE
Libby
Division of Reproductive Sciences, and.
Elise
E
Bales
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
David J
DJ
Orlicky
From the Integrated Physiology Graduate Program, jim.mcmanaman@ucdenver.edu.|Division of Reproductive Sciences, and.
James L
JL
McManaman
D000818:Animals; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000235:genetics / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000235:genetics / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1
endoplasmic reticulum stress (ER stress); gene knockout; lipid droplet; lipid metabolism; lipogenesis; liver metabolism; mass spectrometry (MS); membrane lipid; metabolic disease; perilipin-2
J Lipid Res. 2013 Oct;54(10 ):2745-53
23881913
Adv Nutr. 2011 Jan;2(1):15-22
22211186
Nat Rev Mol Cell Biol. 2008 May;9(5):367-77
18401346
Biochimie. 2014 Jan;96:96-101
24036367
Chem Phys Lipids. 2008 May;153(1):3-13
18343222
Gut. 2011 Oct;60(10):1394-402
21270117
J Cell Biol. 2010 May 31;189(5):783-94
20513765
Dig Liver Dis. 2010 May;42(5):320-30
20207596
J Hepatol. 2014 Aug;61(2):358-65
24768901
J Lipid Res. 2010 Aug;51(8):2132-42
20424269
Nat Med. 2007 Oct;13(10):1193-202
17906635
Gastroenterology. 2007 May;132(5):1947-54
17484887
J Biol Chem. 2010 Jul 16;285(29):22027-35
20489212
J Lipid Res. 2006 Jan;47(1):181-92
16222032
J Lipid Res. 2014 Jul;55(7):1448-64
24814977
J Mol Med (Berl). 2009 Apr;87(4):379-84
19259639
Am J Physiol Gastrointest Liver Physiol. 2008 Sep;295(3):G621-8
18669627
Am J Physiol Gastrointest Liver Physiol. 2006 Sep;291(3):G382-8
16798720
J Lipid Res. 2005 Apr;46(4):706-15
15654130
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3441-6
20133650
Curr Opin Lipidol. 2008 Jun;19(3):295-300
18460922
J Nutr. 1988 Jun;118(6):661-8
2836574
Curr Opin Lipidol. 2010 Feb;21(1):64-9
19809313
J Biol Chem. 2002 Jan 18;277(3):1705-11
11694526
Hepatology. 2003 Dec;38(6):1529-39
14647064
Genes Cells. 2013 Sep;18(9):798-809
23803178
Endocrinology. 2013 Oct;154(10 ):3632-42
23885014
Genes Dev. 2000 Nov 15;14 (22):2819-30
11090130
J Lipid Res. 1999 Sep;40(9):1549-58
10484602
PLoS One. 2010 Dec 16;5(12):e14363
21179554
Clin Chest Med. 2009 Sep;30(3):415-44, vii
19700042
Diabetes. 2009 Aug;58(8):1757-65
19478146
Biochem J. 2005 May 15;388(Pt 1):135-42
15610069
Exp Cell Res. 2016 Jan 15;340(2):187-92
26515554
Biochem Biophys Res Commun. 2014 Jul 18;450(1):117-23
24875360
Nat Med. 2010 Apr;16(4):438-45
20348923
Science. 2008 Jun 13;320(5882):1492-6
18556558
Semin Liver Dis. 2012 Feb;32(1):30-8
22418886
Cytokine Growth Factor Rev. 2003 Oct;14(5):447-55
12948526
Biochim Biophys Acta. 2012 May;1821(5):809-18
22056763
J Clin Invest. 2002 May;109(9):1125-31
11994399
J Hepatol. 2011 Feb;54(2):348-56
21109325
J Biol Chem. 2008 Nov 28;283(48):33772-83
18835813
J Lipid Res. 2013 May;54(5):1346-59
23402988
Mol Cell Biol. 2006 Feb;26(3):1063-76
16428458
Annu Rev Nutr. 2013;33:231-48
23862644
Diabetologia. 2012 Apr;55(4):885-904
22278337
Hepatology. 2012 Dec;56(6):2199-208
22753171
Science. 2004 Oct 15;306(5695):457-61
15486293
J Biol Chem. 1999 Dec 10;274(50):35832-9
10585467
Proc Natl Acad Sci U S A. 2013 Mar 19;110(12 ):4628-33
23487760
Liver Int. 2015 Feb;35(2):582-90
25219574
Biochem Biophys Res Commun. 2012 May 25;422(1):1-4
22575446
Physiol Genomics. 2012 Nov 15;44(22):1125-31
23012396
Curr Opin Cell Biol. 2015 Apr;33:67-73
25543896
Cell Metab. 2008 Sep;8(3):266-74
18762027
J Biol Chem. 2001 Feb 9;276(6):4365-72
11085986
J Cell Sci. 2006 Mar 15;119(Pt 6):973-6
16525117
J Lipid Res. 2016 Mar;57(3):333-5
26798145
J Clin Invest. 2004 Jul;114(2):147-52
15254578
Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):330-44
23507799
J Lipid Res. 2008 Jan;49(1):206-16
17921437
Cell Metab. 2011 Apr 6;13(4):376-88
21459323
Diabetologia. 2005 Apr;48(4):634-42
15747110
J Lipid Res. 2013 Jan;54(1):71-84
23099444
Endocrinology. 2008 Mar;149(3):942-9
18202123
Sci Rep. 2016 Feb 15;6:20975
26876687
J Cell Biol. 2004 Oct 11;167(1):35-41
15466483