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However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results \u2003<\/jats:title>\n                    <jats:p>Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion\u2003<\/jats:title>\n                    <jats:p>FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvab076","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T07:09:36Z","timestamp":1614841776000},"page":"489-502","source":"Crossref","is-referenced-by-count":76,"title":["Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-8953","authenticated-orcid":false,"given":"Cong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Sch\u00f6nke","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3739-4934","authenticated-orcid":false,"given":"Enchen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0014-5571","authenticated-orcid":false,"given":"Sander","family":"Kooijman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00ebtte R","family":"Boon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2561-0046","authenticated-orcid":false,"given":"Mikael","family":"Larsson","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal and Metabolism, AstraZeneca BioPharmaceutical R&D, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3231-2733","authenticated-orcid":false,"given":"Kristina","family":"Wallenius","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal and Metabolism, AstraZeneca BioPharmaceutical R&D, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-6041","authenticated-orcid":false,"given":"Niek","family":"Dekker","sequence":"additional","affiliation":[{"name":"Discovery Sciences, AstraZeneca BioPharmaceutical R&D, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Barlind","sequence":"additional","affiliation":[{"name":"Discovery Sciences, AstraZeneca BioPharmaceutical R&D, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Rong","family":"Peng","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal and Metabolism, AstraZeneca BioPharmaceutical R&D, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":false,"given":"Patrick C N","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, P.O. 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