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PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice.

ABSTRACT: Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.

SUBMITTER: de Jong LM

PROVIDER: S-EPMC8748717 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Long-chain n3-polyunsaturated fatty acids (LC n3-PUFA) are well known for their anti-inflammatory activity and their impact on cardiovascular disease. Cold-pressed whale oil (CWO) has half the amount of LC n3-PUFA compared to cod liver oil (CLO). Still, there has been observed more pronounced beneficial effects on cardiovascular disease markers from intake of CWO compared to intake of CLO in human intervention studies. Extracts from CWO deprived of fatty acids have also been shown to display antioxidative and anti-inflammatory effects in vitro. The aim of this study was to investigate whether intake of a high-fat Western-type diet (WD) supplemented with CWO would prevent the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice. Methods:Seventy female ApoE-/- mice were fed a WD containing 1% CWO, CLO or corn oil (CO). Atherosclerotic lesion formation, body and tissue weights, hepatic gene expression together with serum levels of LDL/VLDL-cholesterol, ox-LDL, total antioxidant status and various serum cardiovascular disease/proinflammatory markers were evaluated. Statistical analyses were performed using SPSS, and Shapiro-Wilk's test was performed to determine the distribution of the variables. Statistical difference was assessed using One-Way ANOVA with Tukeys' post hoc test or Kruskal-Wallis test. The hepatic relative gene expression was analysed with REST 2009 (V2.0.13). Results:Mice fed CWO had less atherosclerotic lesions in the aortic arch compared to mice fed CO. Levels of LDL/VLDL-cholesterol and ox-LDL-cholesterol were also markedly reduced whereas total antioxidant levels were enhanced in mice fed CWO compared to CO-fed mice. In addition, CWO-fed mice gained less weight and several hepatic genes involved in the cholesterol metabolism were up-regulated compared to CO-fed mice. Conclusion:In the present study mice fed a WD supplemented with 1% CWO had reduced formation of atherosclerotic lesions in the aortic arch, reduced serum LDL/VLDL-cholesterol and ox-LDL-cholesterol, increased serum total antioxidant status and reduced body weight compared to mice fed a WD supplemented with 1% CO.

Project description:Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 ?M CuSO4 for 24?h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1?, IL-6, and tumor necrosis factor- (TNF-) ? in a culture medium were determined by ELISA, and the levels of total and phosphorylated I?B, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1?, IL-6, and TNF-? in the medium. The levels of phosphorylated/total I?B, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1?, IL-6, and TNF-?. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-?B and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-?B-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

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PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice.

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