Abstract
Fibroblast growth factor 21 (FGF21) is a newly discovered adipokine, synthesized by several organs, mostly by the liver, which was introduced as a potent metabolic regulator and insulin-sensitizing factor. Numerous animal studies have demonstrated that FGF21 improves glucose and lipids metabolism and exerts anti-inflammatory effects. However, data obtained from human studies have shown contradictory results, in which circulating FGF21 levels were often elevated in obesity, dyslipidemia, type 2 diabetes (DM2) and other conditions connected with insulin resistance. This increase in basal FGF21 concentrations observed in patients with obesity and other conditions related to insulin resistance was being explained as a compensatory response to the underlying metabolic disturbances or tissue resistance to FGF21 action. Furthermore, the results of clinical trials have shown that increased FGF21 concentrations were associated with increased cardiovascular (CV) risk and had a prognostic value in CV outcomes. In recent years, it has been reported that FGF21 may exert cardioprotective effects. This mini-review aims to summarize the current state of knowledge about the role of FGF21 in CV disorders, and discuss the molecular mechanism underlying the anti-atherogenic properties of this compound.
References
1. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627–35.10.1172/JCI23606Search in Google Scholar
2. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203–6.10.1016/S0167-4781(00)00067-1Search in Google Scholar
3. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 2007;104:7432–7.10.1073/pnas.0701600104Search in Google Scholar PubMed PubMed Central
4. Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 2009;150:4931–40.10.1210/en.2009-0532Search in Google Scholar PubMed PubMed Central
5. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774–81.10.1210/en.2006-1168Search in Google Scholar PubMed
6. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008;57:1246–53.10.2337/db07-1476Search in Google Scholar PubMed
7. Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, Tang Y, Liu H, Boden G. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2008;116:65–8.10.1055/s-2007-985148Search in Google Scholar PubMed
8. Li X, Fan X, Ren F, Zhang Y, Shen C, Ren G, Sun J, Zhang N, Wang W, Ning G, Yang J. Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently. Diabetes Res Clin Pract 2011;93:10–6.10.1016/j.diabres.2011.02.034Search in Google Scholar PubMed
9. Jin L, Lin Z, Xu A. Fibroblast growth factor 21 protects against atherosclerosis via fine-tuning the multiorgan crosstalk. Diabetes Metab J 2016;40:22–31.10.4093/dmj.2016.40.1.22Search in Google Scholar PubMed PubMed Central
10. Zhang X, Hu Y, Zeng H, Li L, Zhao J, Zhao J, Liu F, Bao Y, Jia W. Serum fibroblast growth factor 21 levels is associated with lower extremity atherosclerotic disease in Chinese female diabetic patients. Cardiovasc Diabetol 2015;14:32.10.1186/s12933-015-0190-7Search in Google Scholar PubMed PubMed Central
11. Xiao Y, Liu L, Xu A, Zhou P, Long Z, Tu Y, Chen X, Tang W, Huang G, Zhou Z. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 2015;14:72.10.1186/s12933-015-0229-9Search in Google Scholar PubMed PubMed Central
12. Chow WS, Xu A, Woo YC, Tso AW, Cheung SC, Fong CH, Tse HF, Chau MT, Cheung BM, Lam KS. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013;33:2454–9.10.1161/ATVBAHA.113.301599Search in Google Scholar PubMed
13. Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, Jin L, Lian Q, Huang Y, Ding H, Triggle C, Wang K, Li X, Xu A. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 2015;131:1861–71.10.1161/CIRCULATIONAHA.115.015308Search in Google Scholar PubMed PubMed Central
14. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013;17:779–89.10.1016/j.cmet.2013.04.005Search in Google Scholar PubMed
15. Kim JH, Bae KH, Choi YK, Go Y, Choe M, Jeon YH, Lee HW, Koo SH, Perfield JW 2nd, Harris RA, Lee IK, Park KG. Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function. Diabetes Obes Metab 2015;17:161–9.10.1111/dom.12408Search in Google Scholar PubMed
16. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli LA, Sitges M, Giralt M, van Bilsen M, Villarroya F. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013;4:2019.10.1038/ncomms3019Search in Google Scholar PubMed
17. Lenart-Lipińska M, Matyjaszek-Matuszek B, Gernand W, Nowakowski A, Solski J. Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up. Diabetes Res Clin Pract 2013;101:194–200.10.1016/j.diabres.2013.04.010Search in Google Scholar PubMed
18. Ong KL, Januszewski AS, O’Connell R, Jenkins AJ, Xu A, Sullivan DR, Barter PJ, Hung WT, Scott RS, Taskinen MR, Keech AC, Rye KA. The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study. Diabetologia 2015;58:464–73.10.1007/s00125-014-3458-7Search in Google Scholar PubMed
19. Ong KL, Januszewski AS, O’Connell R, Buizen L, Jenkins AJ, Xu A, Sullivan DR, Barter PJ, Scott RS, Taskinen MR, Rye KA, Keech AC; FIELD study. Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study. Diabetologia 2015;58:2035–44.10.1007/s00125-015-3652-2Search in Google Scholar PubMed
20. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013;18:333–40.10.1016/j.cmet.2013.08.005Search in Google Scholar PubMed
21. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, Hernandez-Illas M, Calle RA. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 2015;80:1051–63.10.1111/bcp.12676Search in Google Scholar PubMed PubMed Central
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