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

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). Products of PUFA oxidation are collectively known as oxylipins (OXL), which can also be produced via enzymatic pathways including lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). These bioactive lipids modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models of WD, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b-/-B6). Targeted lipidomic profiling of OXL was performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in livers from 16-week-old male and female mice. In both tx-j and Atp7b-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The marker of oxidative stress, 9-HETE was increased, particularly in tx-j mice. Both genotypes showed higher PUFA-derived alcohols, diols, and ketones with altered epoxides. Expression of Alox5 and Cyp1a1 was upregulated in both mouse models. Pathway analyses show dysregulation in arachidonic acid metabolism characterizes mice with WD. Our findings indicate that early-stage WD is characterized by alterations in hepatic PUFA metabolism and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation via COX and LOX pathways, as well as altered CYP activities. These novel pathways could be potential targets for future therapies.