12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response.
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.
Dept. of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Banumathi K
BK
Cole
Norine S
NS
Kuhn
Shamina M
SM
Green-Mitchell
Kendall A
KA
Leone
Rebekah M
RM
Raab
Jerry L
JL
Nadler
Swarup K
SK
Chakrabarti
D041721:3T3-L1 Cells; D051700:Activating Transcription Factor 3 / Q000096:biosynthesis; D017667:Adipocytes / Q000502:physiology; D052242:Adiponectin / Q000096:biosynthesis; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D002469:Cell Separation; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004822:Epididymis / Q000166:cytology; D007249:Inflammation / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D007515:Islets of Langerhans / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*
C475064:12-15-lipoxygenase; D051700:Activating Transcription Factor 3; D052242:Adiponectin; C103002:Atf3 protein, mouse; D022763:CCAAT-Enhancer-Binding Protein-alpha; D012313:RNA; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase