Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice
Scientific Reports, vol. 11, pp. 16419
Abstract
Total 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.
Authors 12
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Menno Hoekstra corresponding Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. hoekstra@lacdr.leidenuniv.nl
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Baoyan Ren Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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University of Helsinki · Finnish Institute for Health and Welfare · Institute for Molecular Medicine Finland
Affiliation as printed
Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Genomics and Biobank Unit, National Institute for Health and Welfare, Biomedicum 1, Helsinki, Finland
Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland
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Reeni B. Hildebrand Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Finnish Institute for Health and Welfare · Bayer (Finland)
Affiliation as printed
Genomics and Biobank Unit, National Institute for Health and Welfare, Biomedicum 1, Helsinki, Finland
Pharmaceuticals Division, Bayer Oy BOF-PH-MRA-MA, Medical Affairs PO, Espoo, Finland
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Vanessa Frodermann Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Li Zhuang Aachen Division of Endocrinology Department of Medicine, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Mariëtte R. Boon Aachen Division of Endocrinology Department of Medicine, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Janine J. Geerling Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Patrick C.N. Rensen Aachen Division of Endocrinology Department of Medicine, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland
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Miranda Van Eck Aachen Gorlaeus Laboratories Division of BioTherapeutics, Leiden Academic Centre for Drug Research
Affiliation as printed
Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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