Please use this identifier to cite or link to this item: https://doi.org/10.1042/CS20190961
Title: IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease
Authors: Lauretta Low Danwei
Lu Liangjian
CHAN CHANG YIEN 
YANG HE 
Yu,Hanry 
LEE GUAT LAY,CAROLINE 
NG KAR HUI 
YAP HUI KIM 
Keywords: Abcg5
Hypercholesterolemia
Lxra
Pcsk9
interleukin-13
minimal change disease
Issue Date: 31-Jan-2020
Publisher: Portland Press Limited
Citation: Lauretta Low Danwei, Lu Liangjian, CHAN CHANG YIEN, YANG HE, Yu,Hanry, LEE GUAT LAY,CAROLINE, NG KAR HUI, YAP HUI KIM (2020-01-31). IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease 134 (2) : 225-237. ScholarBank@NUS Repository. 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<0.001). The hypercholesterolemia was also contributed by decreased Abcg5 expression and activity, due to reduced Lxra expression. Lxra expression correlated with plasma total cholesterol levels (r=-0.52, p=0.01), and overexpression of pLxra in rat hepatocytes abrogated the IL-13-mediated downregulation of Lxre-driven gene expression. In conclusion, we have shown that IL-13 induced changes in hepatic cholesterol handling in a cytokine-induced rat model of MCD, resulting in hypercholesterolemia which can precede the onset of proteinuria.
URI: https://scholarbank.nus.edu.sg/handle/10635/164810
ISSN: 0143-5221
DOI: 10.1042/CS20190961
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