Analysis of the role of acyl-CoA synthetase long-chain family member 4 in paraquat-induced pulmonary toxicity

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  • パラコートの肺毒性発現における長鎖アシルCoA合成酵素(ACSL)4の役割の解析

Abstract

<p>Acyl-CoA synthetase long-chain family members (ACSLs) are family member of enzymes that catalyze the synthesis of long-chain acyl-CoA from long-chain fatty acids. Among five ACSL isozymes, ACSL4 prefers polyunsaturated fatty acids (PUFAs) such as docosatetraenoic acid and docosahexaenoic acid, in addition to arachidonic acid and eicosapentaenoic acid as its substrate, which are precursors of bioactive lipids such as eicosanoids. Because of this substrate specificity, ACSL4 is assumed to be involved in the incorporation of PUFAs into membrane phospholipids and the production of bioactive lipids such as eicosanoids. Furthermore, the involvement of ACSL4 in cell death and tissue injury has gathered attention. In this study, we examined the effects of ACSL4 deficiency on the membrane phospholipid composition of mouse lung, and then investigated the involvement of ACSL4 in PQ-induced lung injury by using ACSL4-deficient mice. The herbicide paraquat (PQ) is known to cause lung injury through the induction of oxidative stress. Our LC-MS/MS analysis revealed that the levels of most PUFA-containing phosphatidylcholine (PC) phosphatidylethanolamines (PEs) decreased in lungs from ACSL4-deficient mice lung compared to those from WT mice. We further found that ACSL4-deficient mice were protected against PQ-induced lung injury. PQ-induced expressions of pro-inflammatory cytokines and chemokines in lung were suppressed by ACSL4 deficiency. These results indicated that ACSL4 plays critical roles in PQ-induced lung toxicity. </p>

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