Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL (oxLDL), and enhances oxLDL uptake in macrophages. However, the precise underlying mechanism remains to be elucidated. PA is known to induce endoplasmic reticulum (ER) stress in various cell types. Therefore, we investigated whether ER stress is involved in PA-induced LOX-1 upregulation. PA induced ER stress, as determined by phosphorylation of PERK, eIF2α, and JNK, as well as induction of CHOP in macrophage-like THP-1 cells. Inhibitors [4-phenylbutyric acid (PBA), sodium tauroursodeoxycholate (TUDCA), and salubrinal] and small interfering RNA (siRNA) for the ER stress response decreased PA-induced LOX-1 upregulation. Thapsigargin, an ER stress inducer, upregulated LOX-1, which was decreased by PBA and TUDCA. We next examined whether unsaturated FAs could counteract the effect of PA. Both oleic acid (OA) and linoleic acid (LA) suppressed PA-induced LOX-1. Activation of the ER stress response observed in the PA-treated cells was markedly attenuated when the cells were cotreated with OA or LA. In addition, OA and LA suppressed thapsigargin-induced LOX-1 upregulation with reduced activation of ER stress markers. Our results indicate that activation of ER stress is involved in PA-induced LOX-1 upregulation in macrophages, and that OA and LA inhibit LOX-1 induction through suppression of ER stress.

cular disease, nonalcoholic steatohepatitis, nephropathy, and several types of cancer ( 1-3 ). WAT mass is determined by the number and size of adipocytes ( 4, 5 ) regulated by cell differentiation, apoptosis, and lipid droplet (LD) formation (6)(7)(8). Insulin is known to inhibit apoptosis ( 9, 10 ) and increase LD formation ( 11,12 ) in adipocytes. Hyperinsulinemia is associated with weight gain in humans ( 13 ). Insulin signaling in adipocytes is critical for the development of obesity ( 14,15 ). Therefore, it has been suggested that insulin is one of the determinants involved in increasing the WAT mass.Our previous study showed that insulin decreases cell death-inducing DNA fragmentation factor-␣ -like effector (CIDE)A expression and increases CIDEC expression, both of which belong to the CIDE family and play critical roles in apoptosis ( 16,17 ) and LD formation ( 18-21 ), and the differential regulation of these genes is related, at least in part, to insulin-induced anti-apoptosis and LD formation in human adipocytes ( 22 ). Our recent study also showed that insulin regulates CIDEA and CIDEC expression via phosphatidylinositol 3-kinase (PI3K), and regulates expression of each protein via Akt1/2-and c-Jun N-terminal kinase (JNK)2-dependent pathways downstream of PI3K, respectively ( 23 ). These results suggest that insulin regulation of CIDEA and CIDEC contribute separately via different signaling pathways to insulin-induced antiapoptosis and LD formation, leading to increases in the number and size of adipocytes. Adipocyte size is determined by LD formation regulated by glucose uptake, de novo fatty acid synthesis, triacylglycerol synthesis, and lipolysis ( 24,25 ). Previous studies suggested that regulation of CIDEC expression contributes to LD maintenance by modulating lipolysis. However, regulation of other genes Press, March 19, 2013 DOI 10.1194 A novel JNK2/SREBP-1c pathway involved in insulininduced fatty acid synthesis in human adipocytes Abbreviations: ACC1, acetyl-CoA carboxylase 1; ACLY, ATP citrate lyase; CIDE, cell death-inducing DNA fragmentation factor-␣ -like effector; DAPI, 4 ′ ,6 ′ -diamidino-2-phenylindole; Dex, dexamethasone; FAS, fatty acid synthase; IPA, Ingenuity Pathway Analysis; JNK, c-Jun N-terminal kinase; LD, lipid droplet; n-SREBP-1c , nuclear form of sterol regulatory element binding protein-1c; PI3K, phosphatidylinositol 3-kinase; pre-SREBP-1c, precursor form of sterol regulatory element binding protein-1c; siJNK, JNK siRNA; siRNA, small interfering RNA; siSREBP-1, SREBP-1 siRNA; SREBP, sterol regulatory element binding protein; WAT, white adipose tissue. Published, JLR Papers in

No abstract

No abstract

No abstract