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Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice

  • Molecular Toxicology
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Abstract

Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of fatty acid and cholesterol metabolism. A high-cholesterol (HC) diet increases the risk of developing cardiovascular diseases (CVD); however, it is unclear whether the toxic effects of cholesterol involve changes in thrombotic factor expression, and whether PPARα is necessary for such effects. To investigate this possibility, we fed a HC diet to wild-type (WT) and Ppara-null mice and measured cholesterol and triglyceride contents, liver histology, serum/plasma levels of coagulation factors, hepatic expression of the coagulation factors, liver/serum sulfatide levels, hepatic sulfatide metabolism, hepatic expression of lipid transporters, and hepatic oxidative stress and its relating enzymes. In Ppara-null mice, the HC diet caused triglyceride accumulation and exacerbated inflammation and oxidative stress in liver, increased levels of coagulation factors, including tissue factor, plasminogen activator inhibitor-1 and carboxypeptidase B2 in blood and liver, and decreased levels of anti-thrombotic sulfatides in serum and liver. These changes were much less marked in WT mice. These findings imply that cholesterol overload exerts its toxic effects at least in part by enhancing thrombosis, secondary to abnormal hepatic lipid metabolism, inflammation, and oxidative stress. Moreover, we reveal for the first time that PPARα can attenuate these toxic effects by transcriptional regulation of coagulation factors and sulfatides, in addition to its known effects of controlling lipid homeostasis and suppressing inflammation and oxidative stress. Therapies aimed at activating PPARα might prevent HC diet-induced CVD through modulating various pro- and anti-thrombotic factors.

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Acknowledgements

We thank Mark Cleasby, PhD, from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) in Japan (nos. 25460329 and 18K08204).

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Author notes

  1. Yu Lu and Makoto Harada contributed equally to this work.

Authors and Affiliations

  1. Department of Metabolic Regulation, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan

    Yu Lu, Makoto Harada, Yuji Kamijo, Takero Nakajima, Naoki Tanaka & Toshifumi Aoyama

  2. Department of Nephrology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan

    Makoto Harada & Yuji Kamijo

  3. Research Center for the Agricultural Food Industry, Shinshu University, Nagano, Nagano, 380-8553, Japan

    Takero Nakajima & Naoki Tanaka

  4. Department of Food and Health Sciences, The University of Nagano, 8-49-7 Miwa, Nagano, Nagano, 380-8525, Japan

    Eiko Sugiyama

  5. Division of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-Adachigun, Saitama, 362-0806, Japan

    Mamoru Kyogashima

  6. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Frank J. Gonzalez

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  1. Yu Lu
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  2. Makoto Harada
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Correspondence to Yuji Kamijo.

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Lu, Y., Harada, M., Kamijo, Y. et al. Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice. Arch Toxicol 93, 149–161 (2019). https://doi.org/10.1007/s00204-018-2335-4

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