Acyloxyacyl hydrolase modulates depressive-like behaviors through aryl hydrocarbon receptor

Abstract

Corticotropin-releasing factor (CRF) regulates stress responses, and aberrant CRF signals are associated with depressive disorders. Crf expression is responsive to arachidonic acid (AA), where CRF is released from the hypothalamic paraventricular nucleus (PVN) to initiate the hypothalamic-pituitary-adrenal axis, culminating in glucocorticoid stress hormone release. Despite this biological and clinical significance, Crf regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by Aoah, is expressed in the PVN, and Aoah regulates Crf through the aryl hydrocarbon receptor (AhR). We previously showed that AOAH-deficient mice mimicked interstitial cystitis/bladder pain syndrome, a condition frequently associated with comorbid anxiety and depression. With the use of novelty-suppressed feeding and sucrose preference assays to quantify rodent correlates of anxiety/depression, AOAH-deficient mice exhibited depressive behaviors. AOAH-deficient mice also had increased CNS AA, increased Crf expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human Crf promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPARγ). PPARγ did not affect AA-dependent Crf expression in vitro, and conditional Pparγ knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPARγ as a therapeutic target for depression. In contrast, Crf induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional Ahr knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that Aoah is a novel genetic regulator of Crf mediated through AhR, and AhR is a therapeutic target for depression.

AOAH remodels arachidonic acid-containing phospholipid pools in a model of interstitial cystitis pain: A MAPP Network study

“…Since we recently found increased free AA in spinal cords of female AOAH-deficient mice [ 11 ], we examined phospholipid pools of AA female mice. We used an untargeted shotgun lipidomics strategy consisting of the ordered acquisition of mass ion trap detection to investigate differences in phosphatidyl choline and phosphatiyl ethanolamine (PC and PE, respectively) under positive and negative ionization mode of lipids extracted from spinal cord segments S1-S3.…”

“…Although lipidomics showed that sacral spinal cords of female wild type mice contained more AA-containing PE than AOAH-deficient mice, it was unclear whether AOAH could directly modulate the sequestration of AA among CNS phospholipids. Microarray analyses showed that variant 3 of human AOAH (hAOAH3) was highly expressed in the CNS compared to other hAOAH variants [ 5 , 11 , 26 ]. We generated a recombinant lentivirus encoding hAOAH3 and, after confirming that HEK293 cells lack AOAH expression by immunoblotting (not shown), transduced HEK293 cells with AOAH3 or lacZ to obtain the 293 lenti-hAOAH3 and 293 lenti-lacZ cells, respectively.…”

“…N42 cells are a model of hypothalamic neurons generated by immortalization of murine embryonic neurons by SV40 large T antigen (Cellutions Biosystems, Toronto, Canada). We and others have used N42 cells previously to study mechanisms of Crf regulation, a gene known to be responsive to AA and eicosanoids [ 27 – 29 ]. Here, we used CRISPR to generate Aoah -null N42 neurons, using a guide RNA designed to target Exons 9 and 10 common to all functional AOAH isoforms, and we then transduced the Aoah -null N42 neurons with AOAH and lacZ lentiviruses to examine the effects of AOAH on AA distribution among neuronal phospholipids.…”

“…We find that AOAH-deficient mice have increased CNS AA and PGE 2 [ 11 ]. Although the protein(s) encoding AA CoA-independent transferase activity has remained elusive, CoA-independent transferase inhibitors have been used extensively to probe the roles of transferases in AA incorporation and distribution among phospholipids (reviewed in [ 38 ]).…”

“…Increased Aoah expression has even been detected in bladder biopsies from IC patients [ 10 ]. To understand the role of AOAH lipase activity in pelvic pain, we recently examined lipids of the sacral spinal cord and found that AOAH-deficient mice have elevated concentrations of arachidonic acid (AA) and prostaglandin E2 (PGE 2 ) [ 11 ]. These findings are consistent with many clinical studies linking pain to AA and its eicosanoid metabolites including in neuropathic pain and osteoarthritis pain [ 12 , 13 ].…”