Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes

Natasha Z Anita; Felicia Kwan; Si Won Ryoo; Chelsi Major-Orfao; William Z Lin; Shiropa Noor; Krista L Lanctôt; Nathan Herrmann; Paul I Oh; Baiju R Shah; Jeremy Gilbert; Angela Assal; Ilana J Halperin; Ameer Y Taha; Walter Swardfager

doi:10.1016/j.jlr.2023.100395

Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes

J Lipid Res. 2023 Jul;64(7):100395. doi: 10.1016/j.jlr.2023.100395. Epub 2023 May 26.

Authors

Affiliations

¹ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada.
² Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada.
³ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴ Sunnybrook Research Institute, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁵ KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada.
⁶ Sunnybrook Research Institute, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁷ Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁸ Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA; West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, USA; Center for Neuroscience, University of California, Davis, Davis, CA, USA.
⁹ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada. Electronic address: w.swardfager@utoronto.ca.

Abstract

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F_1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F_1,98 = 7.222, P = 0.008 and F_1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F_1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F_1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Keywords: Alzheimer’s disease; inflammation; lipids; obesity; oxidized lipids.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aged
Cognition
Cytochrome P-450 Enzyme System
Diabetes Mellitus, Type 2* / complications
Epoxide Hydrolases / metabolism
Female
Humans
Linoleic Acid* / metabolism
Male
Middle Aged
Obesity / complications
Oxylipins / metabolism

Substances

Linoleic Acid
Oxylipins
Epoxide Hydrolases
Cytochrome P-450 Enzyme System

Grants and funding

PJT-159711/CIHR/Canada