Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations

Tagreed A Mazi; Noreene M Shibata; Gaurav V Sarode; Valentina Medici

doi:10.1016/j.bbalip.2023.159446

Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations

Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Mar;1869(2):159446. doi: 10.1016/j.bbalip.2023.159446. Epub 2023 Dec 9.

Authors

Tagreed A Mazi¹, Noreene M Shibata², Gaurav V Sarode², Valentina Medici³

Affiliations

¹ Department of Community Health Sciences-Clinical Nutrition, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia. Electronic address: tmazi@ksu.edu.sa.
² Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA.
³ Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA. Electronic address: vmedici@ucdavis.edu.

PMID: 38072238
DOI: 10.1016/j.bbalip.2023.159446

Abstract

Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b^-/-B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b^-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Keywords: Copper; Cyclooxygenases; Inflammation; Lipoxygenases; Oxylipins; Reactive oxygen species; Wilson disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Copper / metabolism
Fatty Acids, Unsaturated
Hepatolenticular Degeneration* / genetics
Hepatolenticular Degeneration* / metabolism
Inflammation
Mice
Oxylipins
Prostaglandins

Substances

Oxylipins
Copper
Fatty Acids, Unsaturated
Prostaglandins

Grants and funding

R01 DK104770/DK/NIDDK NIH HHS/United States