LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis

Guo, Xin; Gao, Mingming; Wang, Yunan; Xiao, Lizu; Liu, Yang; Cong, Nathan; An, Xiangbo; Wang, Feng; Qu, Kai; Yu, Liqing; Wang, Yuhui; Wang, Jinjie; Zhu, Haibo; Xia, Xian; Liu, George

doi:10.1016/j.ebiom.2017.12.013

Cited by 62 publications

(72 citation statements)

References 28 publications

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“…Given that this study was performed in the animal model lacking LDLR, these data may be more relevant for humans with familial hypercholesterolemia than for general population. As previously reported by Guo et al, high-fat diet can induce human-like hyperlipidemia in LDLR −/− hamsters [17]. The TC-lowering effect of ezetimibe was consistent with the results obtained from C57BL/6 J mice [13], apolipoprotein E knockout mice [24], rhesus monkeys [6], and humans [10].…”

Section: Discussionsupporting

confidence: 91%

“…The TG-lowering effect of ezetimibe in LDLR −/− hamsters was inconsistent with the data in rhesus monkeys [6], and humans [10]. However, our data were consistent with the previous results obtained in LDLR −/− animals [17,19], which also indicated that ezetimibe not only significantly reduced plasma TC levels but also decreased plasma TG levels. These differences may be attributed to the distinct animal models, and especially the absent of LDLR.…”

Section: Discussioncontrasting

confidence: 58%

“…One of the limitations of the previous studies in mice is that mice are high-density lipoprotein cholesterol (HDL-C) dominant, while humans are non-HDL-C dominant [17]. Furthermore, mice are naturally lack cholesteryl ester transfer protein, which is important for cholesterol metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters

et al. 2020

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Background:The LDL-C lowering effect of ezetimibe has been attributed primarily to increased catabolism of LDL-C via up-regulation of LDL receptor (LDLR) and decreased cholesterol absorption. Recently, ezetimibe has been demonstrated to have reverse cholesterol transport (RCT) promoting effects in mice, hamsters and humans. However, the underlying mechanisms are still not clear. The aim of this study is to investigate whether ezetimibe improves RCT-related protein expression in LDLR −/− hamsters.Methods: A high-fat diet was used to induce a human-like hyperlipidemia in LDLR −/− hamsters. Lipid profiles were assayed by commercially available kits, and the effects of ezetimibe on lipid metabolism-related protein expression were carried out via western blot.Results: Our data demonstrated that ezetimibe administration significantly reduced plasma total cholesterol (5 1.6% reduction, P < 0.01) and triglyceride (from~884.1 mg/dL to~277.3 mg/dL) levels in LDLR −/− hamsters fed a high-fat diet. Ezetimibe administration (25 mg/kg/d) significantly promoted the protein expression of cholesterol 7 alpha-hydroxylase A1 (CYP7A1), LXRβ and peroxisome proliferator-activated receptor (PPAR) γ; and down-regulated the protein expression of PPARα and PPARβ. However, it showed no significant effect on sterol regulatory elementbinding protein (SREBP)-1c, SREBP-2, proprotein convertase subtilisin/kexin type 9 (PCSK9), Niemann-Pick C1-like 1 (NPC1L1), and ATP-biding cassette (ABC) G5/G8. Conclusion:Ezetimibe may accelerate the transformation from cholesterol to bile acid via promoting CYP7A1 and thereby enhance RCT. As a compensatory mechanism of TG lowering, ezetimibe promoted the protein expression of PPARγ and decreased PPARα and β. These results are helpful in explaining the lipid-lowering effects of ezetimibe and the potential compensatory mechanisms.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 58%

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Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters

et al. 2020

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“…This result could be attributed to the inability of traditional machine learning to extract deeper abstract features for prediction, resulting in poor performance, while DLDTI applies a deep convolutional neural network approach and is able to capture the potential structural properties of complex networks and heterogeneous information.Furthermore, in the validation study of the DLDTI model, we used TMPZ (a drug with known structure) to explore its effects on atherosclerosis in vivo. Consistent with previous studies[16][17][18], the results revealed that TMPZ could ameliorate the phenotyping of atherosclerosis in Ldlr-/-hamsters, a novel atherosclerosis model[31][43]. Diminished lipid deposition and macrophage accumulation, and increased percentage of SMC were observed in TMPZ-and clopidogrel-treated hamsters.…”

supporting

confidence: 91%

DLDTI: A Learning-based Framework for Drug-target Interaction Identification Using Neural Networks and Network Representation

Zhao

Zheng

Guan

et al. 2020

Preprint

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Background: Drug repositioning, the strategy of unveiling novel targets of existing drugs could reduce costs and accelerate the pace of drug development. To elucidate the novel molecular mechanism of known drugs, considering the long time and high cost of experimental determination, the efficient and feasible computational methods to predict the potential associations between drugs and targets are of great aid.Methods: A novel calculation model for drug-target interaction (DTI) prediction based on network representation learning and convolutional neural networks, called DLDTI， was generated. The proposed approach simultaneously fuses the topology of complex networks and diverse information from heterogeneous data sources, and copes with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning the low-dimensional and rich depth features of drugs and proteins. The low-dimensional feature vectors were used to train DLDTI to obtain the optimal mapping space and to infer new DTIs by ranking candidates according to their proximity to the optimal mapping space. More specifically, based on the results from the DLDTI, we experimentally validate the predicted targets of tetramethylpyrazine (TMPZ) on atherosclerosis progression in vivo.Results: The experimental results show that the DLDTI model achieves promising performance under 5-fold cross-validations with AUC values of 0.9172, which is higher than the methods using different classifiers or different feature combination methods mentioned in this paper. For the validation study of TMPZ on atherosclerosis, a total of 288 targets were identified and 190 of them were involved in platelet activation. The pathway analysis indicated signaling pathways, namely PI3K/Akt, cAMP and calcium pathways might be the potential targets. Effects and molecular mechanism of TMPZ on atherosclerosis were experimentally confirmed in animal models.Conclusions: DLDTI model can serve as a useful tool to provide promising DTI candidates for experimental validation. Based on the predicted results of DLDTI model, we found TMPZ could attenuate atherosclerosis by inhibiting signal transductions in platelets. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI.

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“…Like humans but unlike like mice, rabbits have abundant plasma cholesteryl ester transfer protein (CETP) activity, intestine-only ApoB mRNA editing, considerable hepatic cholesterol synthesis, and LDL as predominate plasma lipoprotein, and other traits [ 49 , 57 , 58 ]. It is generally better to use an animal model with lipid metabolism mechanisms similar to that of humans.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7

et al. 2018

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Rabbits (Oryctolagus cuniculus) have been the very frequently used as animal models in the study of human lipid metabolism and atherosclerosis, because they have similar lipoprotein metabolism to humans. Most of hyperlipidemia and atherosclerosis rabbit models are produced by feeding rabbits a high-cholesterol diet. Gene editing or knockout (KO) offered another means of producing rabbit models for study of the metabolism of lipids and lipoproteins. Even so, apolipoprotein (Apo)E KO rabbits must be fed a high-cholesterol diet to induce hyperlipidemia.In this study, we used the CRISPR/Cas9 system anchored exon 7 of low-density lipoprotein receptor (LDLR) in an attempt to generate KO rabbits. We designed two sgRNA sequences located in E7:g.7055–7074 and E7:g.7102–7124 of rabbit LDLR gene, respectively. Seven LDLR-KO founder rabbits were generated, and all of them contained biallelic modifications. Various mutational LDLR amino acid sequences of the 7 founder rabbits were subjected to tertiary structure modeling with SWISS-MODEL, and results showed that the structure of EGF-A domain of each protein differs from the wild-type. All the founder rabbits spontaneously developed hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. Analysis of their plasma lipids and lipoproteins at the age of 12 weeks revealed that all these KO rabbits exhibited markedly increased levels of plasma TC (the highest of which was 1013.15 mg/dl, 20-fold higher than wild-type rabbits), LDL-C (the highest of which was 730.00 mg/dl, 35-fold higher than wild-type rabbits) and TG accompanied by reduced HDL-C levels. Pathological examinations of a founder rabbit showed prominent aortic atherosclerosis lesions and coronary artery atherosclerosis.In conclusion, we have reported the generation LDLR-KO rabbit model for the study of spontaneous hypercholesterolemia and atherosclerosis on a NC diet. The LDLR-KO rabbits should be a useful rabbit model of human familial hypercholesterolemia (FH) for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardio-cerebrovascular disease.

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LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis

Cited by 62 publications

References 28 publications

Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters

Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters

DLDTI: A Learning-based Framework for Drug-target Interaction Identification Using Neural Networks and Network Representation

Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7

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