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

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Laura M. de Jong ◽  
Zhengzheng Zhang ◽  
Yvette den Hartog ◽  
Timothy J. P. Sijsenaar ◽  
Renata Martins Cardoso ◽  
...  
Keyword(s):  
Bile Acid ◽  
Hepatic Steatosis ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Skin Lesions ◽  
Plasma Triglyceride ◽  
Bile Acid Metabolism ◽  
Lower Plasma ◽  
Alcoholic Fatty Liver ◽  
Ldl Receptor Knockout Mice

AbstractProtein 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.

scholarly journals Dietary Fruit and Vegetable Supplementation Suppresses Diet-induced Atherosclerosis in LDL Receptor Knockout Mice (OR24-07-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Weimin Guo ◽  
Sharon Kim ◽  
Dayong Wu ◽  
Lijun Li ◽  
Michael Thomas ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Knockout Mice ◽  
Agricultural Research ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Aortic Lesion ◽  
Freeze Dried ◽  
Underlying Mechanisms ◽  
Ldl Receptor Knockout Mice

Abstract Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is inversely associated with incidence of cardiovascular disease (CVD). However, the evidence for causality and underlying mechanisms is lacking. Our objective was to determine if increased consumption of F&V could prevent atherosclerosis and its underlying mechanisms. Methods A unique blend of the most commonly consumed 24 F&V was freeze-dried into a powder and mixed into diets. Thirty six 4-week old male LDL receptor knockout mice were randomly assigned to one of 3 diet groups (12/group): low fat (LF, 10 kcal% fat), high-fat (27 kcal% fat) with 0% F&V (HF), and HF plus 15% F&V diet (HF + FV, equivalent to 8–9 servings for humans). After 20 weeks, mice were euthanized and blood, aorta, and liver tissue were collected. Aortic atherosclerotic lesion, hepatic steatosis, plasma lipid profile and pro-inflammatory cytokine levels were measured. Results No significant differences were found in body weight among the 3 groups. Mice fed HF diet had larger aortic atherosclerotic lesion and hepatic steatosis area than mice fed LF diet by 6.5 and 1.9 fold, respectively (p < 0.001). HF + FV group had 80% less aortic lesion and hepatic steatosis than HF group (p < 0.001). Mice fed HF diet had significantly higher plasma TG and LDL and lower HDL levels than mice fed LF diet, and this dyslipidemia was prevented by F&V supplementation. Further, HF + FV group had lower plasma TNFα levels compared to HF0 group (p < 0.05). Spearman correlation analysis showed that aortic atherosclerotic lesion and hepatic steatosis area were negatively correlated with plasma HDL (p < 0.001) and significantly and positively correlated with TNFα, and the ratios of LDL/HDL, TG/HDL, and non HDL/HDL. Conclusions Our results demonstrate a causal role of high intake of F&V in preventing HF-induced atherosclerosis and hepatic steatosis, which may be mediated through improved dyslipidemia and reduced inflammation. Funding Sources U.S. Department of Agriculture – Agricultural Research Service. Supporting Tables, Images and/or Graphs

scholarly journals PCPE2 and SR-BI Partner to Impact Accumulation of Fat in Mice

2018 ◽  
Author(s):  
Hao Xu ◽  
Sushma Kaul ◽  
Rachel Kallinger ◽  
Michael J. Thomas ◽  
Rebecca L. Schill ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Matrix Protein ◽  
Subcutaneous Fat ◽  
Fatty Acid Distribution ◽  
Ldl Receptor ◽  
Plasma Triglyceride ◽  
Extracellular Matrix Protein ◽  
Fat Pad ◽  
Cell Extracts ◽  
Ldl Receptor Knockout Mice

ABSTRACTLDL receptor knockout mice (LDLr-/-) were crossed with PCPE2 knockout mice to obtain Ldlr-/-,Pcpe2-/- mice. The rationale of these studies was to examine the effects of an extracellular matrix protein, PCPE2, on fat storage in a dyslipidemic mouse model. Male Ldlr-/-, Pcpe2-/- mice were fed a Western diet for 25 weeks and their plasma triglyceride metabolism and triglyceride storage was examined. Interestingly, visceral but not subcutaneous fat pad were smaller in diet-fed Ldlr-/-,Pcpe2-/- mice compared to controls. There was no difference in the fatty acid distribution in triglyceride and cholesteryl esters (CE) among the genotypes. Ldlr-/-, Pcpe2-/- mice have higher plasma triglyceride levels and reduced lipoprotein lipase activity. Immunoprecipitation of SR-BI from cell extracts co-precipitated PCPE2 suggesting that PCPE2 and SR-BI are tightly associated. This work also showed that in the absence of PCPE2 SR-BI does not transfer CE from HDL into the cell. These results suggest that HDL, PCPE2, SR-BI, and possibly LPL are associated in an interactome that is required for CE transport into the cell. In the absence of these interactions lipid transport is significantly disrupted.

Activation of the Nuclear Receptor PXR Decreases Plasma LDL-Cholesterol Levels and Induces Hepatic Steatosis in LDL Receptor Knockout Mice

2008 ◽  
Vol 6 (1) ◽  
pp. 182-189 ◽  
Author(s):  
Menno Hoekstra ◽  
Bart Lammers ◽  
Ruud Out ◽  
Zhaosha Li ◽  
Miranda Van Eck ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Nuclear Receptor ◽  
Knockout Mice ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Cholesterol Levels ◽  
Ldl Receptor Knockout Mice

scholarly journals Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice

2013 ◽  
Vol 111 (6) ◽  
pp. 979-986 ◽  
Author(s):  
Gabriel G. Dorighello ◽  
Juliana C. Rovani ◽  
Christopher J. F. Luhman ◽  
Bruno A. Paim ◽  
Helena F. Raposo ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Plasma Levels ◽  
Food Restriction ◽  
Ldl Receptor ◽  
Intermittent Fasting ◽  
Wild Type ◽  
Obesity And Diabetes ◽  
Ad Libitum ◽  
Atherosclerosis Development ◽  
Ldl Receptor Knockout Mice

Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia.

Wild rice (Zizania palustris L.) prevents atherogenesis in LDL receptor knockout mice

2013 ◽  
Vol 230 (2) ◽  
pp. 284-292 ◽  
Author(s):  
Gangadaran Surendiran ◽  
ChunYan Goh ◽  
Khuong Le ◽  
Zhaohui Zhao ◽  
Fatemeh Askarian ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Wild Rice ◽  
Ldl Receptor ◽  
Zizania Palustris ◽  
Ldl Receptor Knockout Mice

Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

2001 ◽  
Vol 88 (5) ◽  
pp. 506-512 ◽  
Author(s):  
Kazunobu Ishikawa ◽  
Daisuke Sugawara ◽  
Xu-ping Wang ◽  
Kazunori Suzuki ◽  
Hiroyuki Itabe ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Heme Oxygenase 1 ◽  
Lesion Formation ◽  
Ldl Receptor Knockout Mice ◽  
Atherosclerotic Lesion Formation

scholarly journals Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Menno Hoekstra ◽  
Baoyan Ren ◽  
Pirkka-Pekka Laurila ◽  
Reeni B. Hildebrand ◽  
Jarkko Soronen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Functional Expression ◽  
Upstream Stimulatory Factor ◽  
Wild Type Littermate ◽  
Brown Adipose ◽  
Total Body ◽  
Ldl Receptor Knockout Mice

AbstractTotal body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.

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