6-PPD quinine (6-PPDQ) affects intestinal barrier function; however, its underlying mechanisms remain largely unknown. In the current study, we examined the role of reduction in phosphatidic acid synthesis in mediating the toxicity of 6-PPDQ in affecting intestinal barrier function. In Caenorhabditis elegans, 6-PPDQ exposure reduced the phosphatidic acid content, which was accompanied by the decreased expression of acl-5 and acl-6 encoding glycerol-3-phosphate acyltransferase. The RNAi of acl-5 and acl-6 lowered the phosphatidic acid content, enhanced intestinal permeability, and resulted in the increased accumulation of 6-PPDQ. Meanwhile, acl-5 and acl-6 RNAi caused susceptibility to 6-PPDQ toxicity by upregulating the expressions of insulin ligands and receptor genes and downregulating the expressions of daf-16 and its target genes. Moreover, the RNAi of acl-5 and acl-6 elevated the expression of let-363, and the RNAi of let-363 could reduce the expressions of insulin ligand genes and confer resistance to 6-PPDQ toxicity. The double RNAi of acl-5 and acl-6 caused more severe enhanced intestinal permeability and 6-PPDQ toxicity. Therefore, 6-PPDQ exposure potentially disrupts phosphatidic acid synthesis to affect intestinal barrier function by downregulating acl-5 and acl-6 expressions.
Wu et al. (Thu,) studied this question.