Advisor(s)
Natalia Kedishvili
Committee Member(s)
Chad Petit
Jessy Deshane
Kiril Popov
Nabiha Yusuf
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Biochemistry and Molecular Genetics
Date of Award
9-11-2025
Abstract
Oxylipins represent a structurally diverse class of hydroxylated metabolites generated through the oxidation of polyunsaturated fatty acids (PUFAs), functioning as crucial mediators of various physiological processes. While significant advances have been made in understanding oxylipin biosynthetic pathways, enzymatic mechanisms governing their catabolism remain largely unexplored. This study identified and characterized dehydrogenase reductase 9 (DHRS9), previously described as a retinol dehydrogenase, as a novel oxylipin dehydrogenase. Biochemical analyses demonstrated that DHRS9 functions as a broad-spectrum oxylipin dehydrogenase with pronounced catalytic efficiency toward hydroxylated oxylipins, specifically at carbon positions 12 and above. Furthermore, we generated a Dhrs9(-/-) mouse model and observed significantly diminished oxidative capacity toward oxylipin substrates in lung, tracheal, and skin tissues compared to wild-type (WT) counterparts. Additionally, we evaluated two DHRS9 mutations associated with early-onset epilepsy, revealing substantial impairments in protein stability and enzymatic function. Phenotypic characterization of the Dhrs9(-/-) model established DHRS9's protective role in respiratory tissues, where it attenuated tissue damage and leukocyte infiltration following intranasal lipopolysaccharide (LPS) challenge. Collectively, these findings establish DHRS9 as a clinically relevant oxylipin dehydrogenase capable of modulating inflammatory responses, potentially offering new therapeutic targets for inflammatory disorders.
ProQuest ID
Recommended Citation
Wirth, Samuel E., "Characterizing The Role Of Dehydrogenase Reductase 9 In Oxylipin Metabolism" (2025). All ETDs from UAB. 7346.
https://digitalcommons.library.uab.edu/etd-collection/7346
