12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

• Published in: American journal of physiology: endocrinology and metabolism 2012-03, Vol.302 (6), p.E654-E665
• Main Authors: Cole, Banumathi K, Kuhn, Norine S, Green-Mitchell, Shamina M, Leone, Kendall A, Raab, Rebekah M, Nadler, Jerry L, Chakrabarti, Swarup K
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Activating Transcription Factor 3 - biosynthesis; Adipocytes - physiology; Adiponectin - biosynthesis; Animals; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - physiology; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - physiology; Blotting, Western; CCAAT-Enhancer-Binding Protein-alpha - biosynthesis; Cell Differentiation - physiology; Cell Separation; Endoplasmic Reticulum - physiology; Epididymis - cytology; Gene expression; Inflammation - physiopathology; Insulin resistance; Insulin Resistance - physiology; Islets of Langerhans - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Real-Time Polymerase Chain Reaction; RNA - biosynthesis; RNA - genetics; Rodents; Signal Transduction - physiology; Stress response; Stress, Physiological - physiology; Tissues
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00373.2011

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.