title: Distinct gene expression profiles characterize cellular responses to palmitate and oleate.
abstract: Obese individuals are both insulin resistant and have high levels of circulating free fatty acids (FFAs). In cell culture, saturated but not unsaturated fatty acids induce endoplasmic reticulum (ER) stress. We hypothesized that chronic exposure to low dose fatty acids would significantly attenuate the acute stress response to a saturated fatty acid challenge and that unsaturated fatty acids (oleate) would be more protective than saturated fatty acids (palmitate). The ER stress response to palmitate was reduced after low dose fatty acid exposure in human hepatoma cells. Palmitate and oleate gave distinctive transcript responses, both acutely and after chronic low dose exposure. Differentially regulated pathways included lipid, cholesterol, fatty acid, and triglyceride metabolism, and IkappaB kinase and nuclear factor kappaB kinase inflammatory cascades. Oleate reduced palmitate-induced changes significantly more than low dose palmitate and completely blocked palmitate-induced phosphoinositide 3 kinase inhibitor (PIK3IP1) as well as induction of GADD45A and B. These changes are predicted to alter the PI3 kinase pathway and the pro-apoptotic p38 MAPK pathway. We recapitulated the oleate response by small interfering RNA-mediated block of PIK3IP1 stimulation with palmitate and significantly protected cells from palmitate-mediated ER stress. We show that transcriptional responses to oleate and palmitate are distinct, broad, and often discordant. We identified several potential candidates that may direct the transcriptional networks and demonstrate that PIK3IP1 partially accounts for the protective effects of oleate.
authors.affiliation: Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. sdas@wfubmc.edu
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Das
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Mondal
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D023281:Genomics; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013997:Time Factors
chemical_list: D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C521076:PIK3IP1 protein, human; D010168:Palmitates; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019301:Oleic Acid
references.citation: BMC Syst Biol. 2007 May 11;1:21
references.pmid: 17498300
references.citation: J Clin Endocrinol Metab. 2006 Nov;91(11):4689-95
references.pmid: 16926257
references.citation: Bioinformatics. 2005 Apr 1;21(7):1280-1
references.pmid: 15546938
references.citation: J Nutr. 2004 Sep;134(9):2444S-2449S
references.pmid: 15333740
references.citation: Biochem Soc Trans. 2008 Oct;36(Pt 5):959-62
references.pmid: 18793169
references.citation: J Endocrinol. 2008 Jun;197(3):553-63
references.pmid: 18492819
references.citation: Nat Rev Immunol. 2008 Dec;8(12):923-34
references.pmid: 19029988
references.citation: Nat Rev Mol Cell Biol. 2008 May;9(5):367-77
references.pmid: 18401346
references.citation: Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1590-8
references.pmid: 17264230
references.citation: Biochem Biophys Res Commun. 2005 Mar 11;328(2):432-41
references.pmid: 15694366
references.citation: J Clin Endocrinol Metab. 2008 Nov;93(11):4532-41
references.pmid: 18728164
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: Biochim Biophys Acta. 2007 Sep;1770(9):1283-8
references.pmid: 17658692
references.citation: Mol Cell Biol. 2007 Apr;27(7):2765-76
references.pmid: 17242196
references.citation: Apoptosis. 2004 Sep;9(5):599-607
references.pmid: 15314288
references.citation: J Clin Invest. 2008 Jan;118(1):316-32
references.pmid: 18060040
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Diabetes. 1994 Nov;43(11):1353-7
references.pmid: 7926311
references.citation: Endocrinology. 2006 Jul;147(7):3398-407
references.pmid: 16601139
references.citation: Am J Physiol Endocrinol Metab. 2008 Mar;294(3):E540-50
references.pmid: 18198352
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: JAMA. 2006 Apr 5;295(13):1549-55
references.pmid: 16595758
references.citation: J Lipid Res. 2006 Dec;47(12):2726-37
references.pmid: 16960261
references.citation: Diabetes. 2009 Feb;58(2):337-43
references.pmid: 19008343
references.citation: Metabolism. 2002 Nov;51(11):1471-7
references.pmid: 12404200
references.citation: Br J Nutr. 2009 Dec;102(11):1557-63
references.pmid: 19622194
references.citation: Nutr Res. 2008 Oct;28(10):681-9
references.pmid: 19083476
references.citation: BMC Genomics. 2007 Oct 09;8:364
references.pmid: 17925029
references.citation: Biochem Biophys Res Commun. 2007 Jun 22;358(1):66-72
references.pmid: 17475214
references.citation: J Lipid Res. 2008 Jan;49(1):84-97
references.pmid: 17951222
references.citation: PLoS Biol. 2006 Nov;4(11):e374
references.pmid: 17090218
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):193-205
references.pmid: 18200017
references.citation: Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E275-81
references.pmid: 16492686
references.citation: J Cell Sci. 2008 Jul 15;121(Pt 14):2308-18
references.pmid: 18559892
references.citation: Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E393-400
references.pmid: 18544642
references.citation: Diabetes. 2007 Dec;56(12):2973-81
references.pmid: 17827403
references.citation: Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E576-86
references.pmid: 17519282
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W186-92
references.pmid: 17526521