Lauretta D. Low, Liangjian Lu, Chang-Yien Chan, Jinmiao Chen, Henry H. Yang, Hanry Yu, Caroline G.L. Lee, Kar-Hui Ng, Hui-Kim Yap; IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease. Clin Sci (Lond) 31 January 2020; 134 (2): 225–237. doi: https://doi.org/10.1042/CS20190961
Abstract:
Circulating factors have been implicated in the pathogenesis of minimal change disease (MCD), and may have direct effects on cholesterol metabolism. This study investigated the pathogenesis of hypercholesterolemia in an IL-13 overexpression rat model of MCD prior to the onset of proteinuria, so as to establish the direct contribution of IL-13, especially with regard to hepatic cholesterol handling. In this model of MCD, the temporal relationship between hypercholesterolemia and proteinuria was first identified. Plasma Pcsk9 and liver Abcg5 were measured using ELISA. Liver Ldlr and Lxra were quantified with Western blot. Abcg5-mediated cholesterol efflux in IL-13-stimulated rat primary hepatocytes was measured using taurocholate as cholesterol acceptor. The role of Lxra was validated using a luciferase assay in Lxre-luciferase-transfected IL-13-stimulated hepatocytes. IL-13-transfected rats developed hypercholesterolemia prior to proteinuria, with 35% of rats hypercholesterolemic but only 11% proteinuric by Day 20 (p=0.04). These pre-proteinuric hypercholesterolemic rats showed elevations in total and LDL-cholesterol, but not hypertriglyceridemia or hepatic steatosis. The hypercholesterolemia was associated with increased hepatic Pcsk9 synthesis and enhanced circulating Pcsk9 levels, which correlated strongly with plasma total cholesterol (r=0.73, p
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Funding Info:
National Medical Research Council, Singapore, National Kidney Foundation, Singapore, and Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR).