Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A novel mouse model of familial combined hyperlipidemia and atherosclerosis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg−1·d−1) and fenofibrate (100 mg·kg−1·d−1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A new mouse model of familial combined hyperlipidemia (FCHL) and atherosclerosis suitable for the evaluation of potential pharmaceutical agents.

References

  1. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gill PK, Hegele RA. Familial combined hyperlipidemia is a polygenic trait. Curr Opin Lipidol. 2022;33:126–32.

    Article  CAS  PubMed  Google Scholar 

  3. Luijten J, Greevenbroek MMJ, Schaper NC, Meex SJR, Steen C, Meijer LJ, et al. Incidence of cardiovascular disease in familial combined hyperlipidemia: A 15-year follow-up study. Atherosclerosis. 2019;280:1–6.

    Article  CAS  PubMed  Google Scholar 

  4. Austin MA, McKnight B, Edwards KL, Bradley CM, McNeely MJ, Psaty BM, et al. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study. Circulation. 2000;101:2777–82.

    Article  CAS  PubMed  Google Scholar 

  5. Wu Q, Huang Y, Kong X, Jia B, Lu X, Chen Y, et al. QDBLiPro: a database for lipids and proteins in human lipid metabolism. Phenomics. 2023;3:350–9.

    Article  CAS  PubMed  Google Scholar 

  6. Braamskamp MJAM, Wijburg FA, Wiegman A. Drug therapy of hypercholesterolaemia in children and adolescents. Drugs. 2012;72:759–72.

    Article  CAS  PubMed  Google Scholar 

  7. Packard CJ, Pirillo A, Tsimikas S, Ferenve BA, Catapano AL. Exploring apolipoprotein C-III: pathophysiological and pharmacological relevance. Cardiovasc Res. 2024;119:2843–57.

  8. Taskinen M-R, Borén J. Why is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep. 2016;18:59.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017;544:235–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 2000;102:1886–92.

    Article  CAS  PubMed  Google Scholar 

  11. Zheng C. Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr Opin Lipidol. 2014;25:35–39.

    Article  CAS  PubMed  Google Scholar 

  12. Luc G, Fievet C, Arveiler D, Evans AE, Bard JM, Cambie F, et al. Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Témoins sur ‘Infarctus du Myocarde. J Lipid Res. 1996;37:508–17.

    Article  CAS  PubMed  Google Scholar 

  13. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–6.

    Article  PubMed  Google Scholar 

  14. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019;381:531–42.

    Article  CAS  PubMed  Google Scholar 

  15. Li H, Han Y, Qi R, Wang Y, Zhang X, Yu M, et al. Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: the effect of authentic triglyceride-rich lipoproteins with and without ApoCIII. Cardiovasc Res. 2015;107:579–89.

    Article  PubMed  Google Scholar 

  16. Zha Y, Lu Y, Zhang T, Yan K, Zhuang W, Liang J, et al. CRISPR/Cas9-mediated knockout of APOC3 stabilizes plasma lipids and inhibits atherosclerosis in rabbits. Lipids Health Dis. 2021;20:180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guo M, Xu Y, Dong Z, Zhou Z, Cong N, Gao M, et al. Inactivation of ApoC3 by CRISPR/Cas9 protects against atherosclerosis in hamsters. Circ Res. 2020;127:1456–8.

    Article  CAS  PubMed  Google Scholar 

  18. Masucci-Magoulas L, Goldberg IJ, Bisgaier CL, Serajuddin H, Francone OL, Breslow JL, et al. A mouse model with features of familial combined hyperlipidemia. Science. 1997;275:391–4.

    Article  CAS  PubMed  Google Scholar 

  19. Bjørklund MM, Hollensen AK, Hagensen MK, Dagnaes-Hansen F, Christoffersen C, Mikkelsen JG, et al. Induction of atherosclerosis in mice and hamsters without germline genetic engineering. Circ Res. 2014;114:1684–9.

    Article  PubMed  Google Scholar 

  20. Centa M, Ketelhuth DFJ, Malin S, Gistera A. Quantification of atherosclerosis in mice. J Vis Exp. 2019; https://doi.org/10.3791/59828.

  21. Hu W, Li M, Sun W, Li Q, Xi H, Qiu Y, et al. Hirsutine ameliorates hepatic and cardiac insulin resistance in high-fat diet-induced diabetic mice and in vitro models. Pharmacol Res. 2022;177:105917.

    Article  CAS  PubMed  Google Scholar 

  22. Nagy C, Einwallner E. Study of in vivo glucose metabolism in high-fat diet-fed mice using oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). J Vis Exp. 2018;56672. https://doi.org/10.3791/56672.

  23. Xu S, Liu Y, Ding Y, Luo S, Zheng X, Wu X, et al. The zinc finger transcription factor, KLF2, protects against COVID-19-associated endothelial dysfunction. Signal Transduct Target Ther. 2021;6:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu S, Wu X, Wang S, Xu M, Fang T, Ma X, et al. TRIM56 protects against non-alcoholic fatty liver disease via promoting the degradation of fatty acid synthase. J Clin Invest. 2024;134:e166149.

  25. Kanter JE, Shao B, Kramer F, Barnhart S, Shimizu-Albergine M, Vaisar T, et al. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. J Clin Invest. 2019;129:4165–79.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Guo J, Meng F, Ma N, Li C, Ding Z, Wang H, et al. Meta-analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia. Am J Cardiol. 2012;110:1296–301.

    Article  CAS  PubMed  Google Scholar 

  27. Geng Q, Ren J, Li S, Chen H. A meta-analysis on the safety of combination 27 therapy with fenofibrate and statins. Zhonghua Xin Xue Guan Bing Za Zhi. 2013;41:1063–8.

    PubMed  Google Scholar 

  28. Geng Q, Ren J, Chen H, Lee C, Liang W. Adverse events following statin-fenofibrate therapy versus statin alone: a meta-analysis of randomized controlled trials. Clin Exp Pharmacol Physiol. 2013;40:219–26.

    Article  CAS  PubMed  Google Scholar 

  29. Ilyas I, Little PJ, Liu Z, Xu Y, Kamato D, Berk BC, et al. Mouse models of atherosclerosis in translational research. Trends Pharmacol Sci. 2022;43:920–39.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Key R&D Program of China (Grant No. 2021YFC2500500), the National Natural Science Foundation of China (Grant No. 82370444, 82070464, 82003741, 82270479, 82070460) and the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB38010100). This work was also supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC (CXGG02), Anhui Provincial Key Research and Development Program (Grant No. 202104j07020051), Anhui Provincial Natural Science Foundation (Grant No. 2208085J08). Suo-wen Xu is the recipient of Humboldt Fellowship for Experienced Researchers from the Alexander von Humboldt Foundation, Germany.

Author information

Author notes

  1. These authors contributed equally: Mei-jie Chen, Yi-tong Xu

Authors and Affiliations

  1. Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230022, China

    Mei-jie Chen, Lu Sun, Zhi-hua Wang, Jian-ping Weng & Suo-wen Xu

  2. Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, 100091, China

    Yi-tong Xu & Xun-de Xian

  3. School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD, 4102, Australia

    Peter J. Little

  4. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

    Li Wang

Authors
  1. Mei-jie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-tong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-hua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter J. Little
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xun-de Xian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian-ping Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Suo-wen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xun-de Xian, Jian-ping Weng or Suo-wen Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Mj., Xu, Yt., Sun, L. et al. A novel mouse model of familial combined hyperlipidemia and atherosclerosis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01241-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-024-01241-8

Keywords

Search

Advanced search

Quick links