Distinct gene expression profiles characterize cellular responses to palmitate and oleate.
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.
Das
Swapan K
SK
Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. sdas@wfubmc.edu
Mondal
Ashis K
AK
Elbein
Steven C
SC
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
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
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