Effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low-density lipoproteins in isolated perfused rat livers

Authors: WALKER, RACHEL - Pennsylvania State University; SAVINOVA, OLGA - New York Institute Of Technology; PEDERSEN, THERESA - University Of California, Davis; Newman, John; SHEARER, GREGORY - Pennsylvania State University

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2020
Publication Date: 2/24/2021
Citation: Walker, R.E., Savinova, O.V., Pedersen, T.L., Newman, J.W., Shearer, G.C. 2021. Effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low-density lipoproteins in isolated perfused rat livers. Physiological Reports. 9(4). Article e14480. https://doi.org/10.14814/phy2.14480.
DOI: https://doi.org/10.14814/phy2.14480

Interpretive Summary: Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular constriction/relaxation, metabolic hemostasis and the formation of blood clots. Very low-density lipoproteins (VLDL) particles are formed in the liver and transport energy in the form of triglycerides to the tissues of the body. These particles contain oxylipins, but it is unknown whether the liver regulates their concentrations or if they are accumulated or formed once the particles enter the blood stream. In this study, we used a perfused liver model to observe the effect of exposure to lipopolysaccharide (LPS; lipid-sugar complexes from bacterial surfaces) which promote inflammation and compounds that inhibit the soluble epoxide hydrolase (sEHi; anti-inflammatory agents) on VLDL oxylipins. A compartmental model of linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased total fatty acid VLDL content by 6 - 47%%, along with several oxylipins by a similar amount including alpha-linolenic acid-derived alcohols (4 - 55%) and epoxides (3% - 49%), and diols of arachidonic acid and docosahexaenoic acid (DHA)-derived (~5% - 50%). However, the eicosapentaenoic-derived epoxide, 17(18)-EpETE, was decreased by ~50% - 90% by LPS, double that of other oxylipins. Exposure to the sEHi increased the DHA epoxide, 16(17)-EpDPE concentration by 35% - 193%. Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by both LPS challenge and inhibition of the epoxide hydrolase pathway. This work provides evidence for the regulated delivery of systemic oxylipin signals by VLDL transport.

Technical Abstract: Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis and thrombosis. Very low-density lipoproteins (VLDL) contain oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL oxylipins. A compartmental model of linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several oxylipins by a similar amount (13-HOTrE, 35% [4%,55%]; 9(10)-EpODE, 29% [3%,49%]; 15(16)-EpODE, 29% [2%,49%]; AA-derived diols, 32% [5%,52%]; 19(20)-DiHDPA, 31% [7%,50%]). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%] with LPS, double the suppression of other oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%]. Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.