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Alterations of lipid metabolism, blood pressure and fatty liver in spontaneously hypertensive rats transgenic for human cholesteryl ester transfer protein

Hypertension Research volume 43, pages 655–666 (2020)Cite this article

Abstract

Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transgenic rodent models thus far. As the results of pharmacological studies of CETP modification are largely controversial in humans, further knowledge about the impact of CETP on atherogenic phenotypes is required to evaluate its clinical utility for the prevention of cardiovascular and other organ damage associated with metabolic syndrome. Therefore, we newly generated a human CETP-transgenic (Tg[hCETP]) strain on the genetic background of spontaneously hypertensive rats (SHRs), which are characterized by the spontaneous occurrence of hypertension and insulin resistance. This allowed us to assess the in vivo role of CETP on cardiometabolic phenotypes in combination with hypertension. In Tg[hCETP] SHRs fed normal rat chow, systolic blood pressure was markedly elevated by 20–37 mmHg throughout the study period, and the development of fatty liver was accelerated with appreciable changes in the plasma lipid profile (HDL cholesterol reduction and triglyceride elevation). These phenotypic changes are in accordance with the assumption of proatherogenic effects inducible by the overexpression of CETP. However, with plasma LDL cholesterol levels concomitantly reduced, no apparent progression of atherosclerosis was detected in either the aorta or coronary arteries of Tg[hCETP] SHRs fed a high-fat, high-cholesterol diet. Our data provide new insight into the multifaceted regulation of cardiometabolic phenotypes via the modification of CETP.

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Data availability

Microarray data have been deposited at the ArrayExpress Archive of Functional Genomics Data, which is hosted by the EMBL-EBI, under accession number [E-MTAB-7861].

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Acknowledgements

We are grateful to Koichi Akiyama of the Research Institute, National Center for Global Health and Medicine, for his technical assistance with DNA analysis. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding

This study was supported by a grant from the National Center for Global Health and Medicine and JSPS KAKENHI Grant no. 26290067.

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Authors and Affiliations

  1. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, 1628655, Japan

    Yi-Qiang Liang, Masato Isono, Fumihiko Takeuchi & Norihiro Kato

  2. Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, 1628655, Japan

    Tadashi Okamura

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  1. Yi-Qiang Liang
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NK conceived and designed the study and wrote the manuscript. Y-QL, MI, and TO performed the experimental analyses. FT performed the data analyses. All authors reviewed the manuscript.

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Correspondence to Norihiro Kato.

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Liang, YQ., Isono, M., Okamura, T. et al. Alterations of lipid metabolism, blood pressure and fatty liver in spontaneously hypertensive rats transgenic for human cholesteryl ester transfer protein. Hypertens Res 43, 655–666 (2020). https://doi.org/10.1038/s41440-020-0401-9

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