The research advance of fibroblast growth factor 21 in anti-atherosclerosis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

XIE Yong ¹ , LI Dongze ¹ , LI Fanghui ² , LU Guangwen ³ ,  CAO Yu ¹

1. Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;
2. West China School of Medicine, Sichuan University, Chengdu, 610041, P.R.China;
3. State Key Laboratory of Biological Treatment of West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;

Corresponding author：

CAO Yu, Email: yuyuer@126.com

Keywords：

Fibroblast growth factor 21; atherosclerosis; biomarker

DOI：

10.7507/1007-4848.201801013

Video：

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Fibroblast growth factor 21 (FGF21) is a multi-effect endocrine factor, mainly secreted in liver and adipose tissue, with the properties of lipid-lowering, anti-inflammatory, anti-oxidant and anti-atherosclerosis. Recent studies found that FGF21 can induce protective effect in cardiovascular disease, and plasma FGF21 levels in patients with disease cardiovascular are elevated. These studies have suggested the use of FGF21 as a biomarker for subclinical atherosclerosis and its potential role in the treatment of established atherosclerotic cardiovascular disease. This article will review the recent advances in the anti-atherosclerosis effect of FGF21.

Citation： XIE Yong, LI Dongze, LI Fanghui, LU Guangwen, CAO Yu. The research advance of fibroblast growth factor 21 in anti-atherosclerosis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2018, 25(5): 434-439. doi: 10.7507/1007-4848.201801013 Copy

1.	Roth GA, Forouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med, 2015, 372(14): 1333-1341.
2.	Woo YC, Xu A, Wang Y, et al. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol (Oxf.), 2013, 78(4) :489-496.
3.	Jin L, Lin Z, Xu A. Fibroblast growth factor 21 protects against atherosclerosis via fine-tuning the multiorgan crosstalk. Diabetes Metab J, 2016, 40(2): 22-31.
4.	Erickson A, Moreau R. The regulation of FGF21 gene expression by metabolic factors and nutrients. Horm Mol Biol Clin Investig, 2016, 30(1): pii: /j/hmbci.2017.30.issue-1/hmbci-2016-0016/hmbci-2016-0016.xml. doi: 10.1515/hmbci-2016-0016.
5.	Adams AC, Astapova I, Fisher FM, et al. Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner. J Biol Chem, 2010, 285(19): 14078-14082.
6.	Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr, 2011, 93(4): 901S-905S.
7.	Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem, 2010, 285(21): 15668-15673.
8.	Cyphert H, Alonge K, Ippagunta S, et al. Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PLoS One, 2014, 9(4): e94996.
9.	Girer NG, Murray IA, Omiecinski CJ, et al. Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression. J Biol Chem, 2016, 291(29): 15378-15387.
10.	Chen X, Li G, Dong Q, et al. miR-577 inhibits pancreatic beta-cell function and survival by targeting fibroblast growth factor 21(FGF-21) in pediatric. Genet Mol Res, 2015, 14(4): 15462-15470.
11.	Lin Z, Pan X, Wu F, et al. 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(21): 1861-1871.
12.	Lin Z, Tian H, Lam KS, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab, 2013, 17(5) :779-789.
13.	Dutchak PA, Katafuchi T, Bookout AL, et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell, 2012, 148(3): 556-567.
14.	Zhu W, Wang C, Liu L, et al. Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo. Can J Physiol Pharmacol, 2014, 92(11): 927-935.
15.	Zhu S, Ma L, Wu Y, et al. FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway. Acta Biochim Biophys Sin, 2014, 46(12): 1041-1048.
16.	Singhal G, Fisher FM, Chee MJ, et al. Fibroblast growth factor 21(FGF21) protects against high fat diet induced inflammation and islet hyperplasia in pancreas. PLoS One, 2016, 11(2): e0148252.
17.	Wang WF, Li SM, Ren GP, et al. Recombinant murine fibroblast growth factor 21 ameliorates obesity-related inflammation in monosodium glutamate-induced obesity rats. Endocrine, 2015, 49(1): 119-129.
18.	Yu Y, He J, Li S, et al. Fibroblast growth factor 21(FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-kappaB signaling pathway. Int Immunopharmacol, 2016, 38: 144-152.
19.	Nakanishi Y, Tsuneyama K, Fujimoto M, et al. Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia. J Autoimmun, 2008, 30(1-2): 42-50.
20.	Wang XM, Song SS, Xiao H, et al. Fibroblast growth factor 21 protects against high glucose induced cellular damage and dysfunction of endothelial nitricoxide synthase in endothelial cells. Cell Physiol Biochem, 2014, 34(3): 658-671.
21.	Gimbrone MA Jr, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res, 2016, 118(4): 620-636.
22.	Chen C, Cheung BM, Tso AW, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care, 2011, 34(9): 2113-2115.
23.	Xiao Y, Liu L, Xu A, et al. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol, 2015, 14: 72.
24.	赵江波, 陈霞, 杨玲, 等. 成纤维细胞因子 21 同腹型肥胖者颈动脉内膜中层厚度及胰岛素抵抗关系的研究. 检验医学与临床, 2016, 13(14): 1929-1930.
25.	An SY, Lee MS, Yi SA, et al. Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques. Diabetes Res Clin Pract, 2012, 96(2): 196-203.
26.	Kim WJ, Kim SS, Lee HC, et al. Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes. J Korean Med Sci, 2015, 30(5): 586-590.
27.	Lenart-Lipinska M, Matyjaszek-Matuszek B, Gernand W, et al. 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(2): 194-200.
28.	刘洋, 俞静. 2 型糖尿病合并动脉粥样硬化患者血清 FGF-21 的变化及意义. 中国医学工程, 2015, 23(7): 81-82.
29.	Chow WS, Xu A, Woo YC, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol, 2013, 33(10): 2454-2459.
30.	陈海峰, 吴峰, 卢楠, 等. 血清成纤维细胞生长因子 21、脂联素与冠状动脉性心脏病的相关性. 中华高血压杂志, 2016, 24(8): 758-762.
31.	郭功亮, 吴金义, 张蕾, 等. 中国成年人血清 FGF21 水平与冠心病风险. 中国老年学杂志, 2015, 3(35): 1233-1235.
32.	颜云宙, 黄伟萍, 陈捷, 等. 老年糖尿病并冠心病患者血清成纤维细胞生长因子 21 与脂联素的检测意义. 中国乡村医药, 2016, 23(5): 64-65.
33.	Shen Y, Ma X, Zhou J, et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol, 2013, 12: 124.
34.	Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab, 2013, 18(3): 333.
35.	Huang J, Ishino T, Chen G, et al. Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther, 2013, 346(2): 270-280.
36.	Talukdar S, Zhou Y, Li D, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab, 2016, 23(2): 427-440.
37.	Dong JQ, Rossulek M, Somayaji VR, et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 minetic,in a first-in-human study. Rr J Clin Pharmacol, 2015, 80(5): 1051.
38.	Videla LA, Fernandez V, Vargas R, et al. Upregulation of rat liver PPARalphaFGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol. Biofactors, 2016, 42(6): 638-646.
39.	Lee Y, Lim S, Hong ES, et al. Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol(Oxf), 2014, 80(1): 57-64.

1. Roth GA, Forouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med, 2015, 372(14): 1333-1341.
2. Woo YC, Xu A, Wang Y, et al. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol (Oxf.), 2013, 78(4) :489-496.
3. Jin L, Lin Z, Xu A. Fibroblast growth factor 21 protects against atherosclerosis via fine-tuning the multiorgan crosstalk. Diabetes Metab J, 2016, 40(2): 22-31.
4. Erickson A, Moreau R. The regulation of FGF21 gene expression by metabolic factors and nutrients. Horm Mol Biol Clin Investig, 2016, 30(1): pii: /j/hmbci.2017.30.issue-1/hmbci-2016-0016/hmbci-2016-0016.xml. doi: 10.1515/hmbci-2016-0016.
5. Adams AC, Astapova I, Fisher FM, et al. Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner. J Biol Chem, 2010, 285(19): 14078-14082.
6. Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr, 2011, 93(4): 901S-905S.
7. Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem, 2010, 285(21): 15668-15673.
8. Cyphert H, Alonge K, Ippagunta S, et al. Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PLoS One, 2014, 9(4): e94996.
9. Girer NG, Murray IA, Omiecinski CJ, et al. Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression. J Biol Chem, 2016, 291(29): 15378-15387.
10. Chen X, Li G, Dong Q, et al. miR-577 inhibits pancreatic beta-cell function and survival by targeting fibroblast growth factor 21(FGF-21) in pediatric. Genet Mol Res, 2015, 14(4): 15462-15470.
11. Lin Z, Pan X, Wu F, et al. 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(21): 1861-1871.
12. Lin Z, Tian H, Lam KS, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab, 2013, 17(5) :779-789.
13. Dutchak PA, Katafuchi T, Bookout AL, et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell, 2012, 148(3): 556-567.
14. Zhu W, Wang C, Liu L, et al. Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo. Can J Physiol Pharmacol, 2014, 92(11): 927-935.
15. Zhu S, Ma L, Wu Y, et al. FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway. Acta Biochim Biophys Sin, 2014, 46(12): 1041-1048.
16. Singhal G, Fisher FM, Chee MJ, et al. Fibroblast growth factor 21(FGF21) protects against high fat diet induced inflammation and islet hyperplasia in pancreas. PLoS One, 2016, 11(2): e0148252.
17. Wang WF, Li SM, Ren GP, et al. Recombinant murine fibroblast growth factor 21 ameliorates obesity-related inflammation in monosodium glutamate-induced obesity rats. Endocrine, 2015, 49(1): 119-129.
18. Yu Y, He J, Li S, et al. Fibroblast growth factor 21(FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-kappaB signaling pathway. Int Immunopharmacol, 2016, 38: 144-152.
19. Nakanishi Y, Tsuneyama K, Fujimoto M, et al. Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia. J Autoimmun, 2008, 30(1-2): 42-50.
20. Wang XM, Song SS, Xiao H, et al. Fibroblast growth factor 21 protects against high glucose induced cellular damage and dysfunction of endothelial nitricoxide synthase in endothelial cells. Cell Physiol Biochem, 2014, 34(3): 658-671.
21. Gimbrone MA Jr, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res, 2016, 118(4): 620-636.
22. Chen C, Cheung BM, Tso AW, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care, 2011, 34(9): 2113-2115.
23. Xiao Y, Liu L, Xu A, et al. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol, 2015, 14: 72.
24. 赵江波, 陈霞, 杨玲, 等. 成纤维细胞因子 21 同腹型肥胖者颈动脉内膜中层厚度及胰岛素抵抗关系的研究. 检验医学与临床, 2016, 13(14): 1929-1930.
25. An SY, Lee MS, Yi SA, et al. Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques. Diabetes Res Clin Pract, 2012, 96(2): 196-203.
26. Kim WJ, Kim SS, Lee HC, et al. Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes. J Korean Med Sci, 2015, 30(5): 586-590.
27. Lenart-Lipinska M, Matyjaszek-Matuszek B, Gernand W, et al. 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(2): 194-200.
28. 刘洋, 俞静. 2 型糖尿病合并动脉粥样硬化患者血清 FGF-21 的变化及意义. 中国医学工程, 2015, 23(7): 81-82.
29. Chow WS, Xu A, Woo YC, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol, 2013, 33(10): 2454-2459.
30. 陈海峰, 吴峰, 卢楠, 等. 血清成纤维细胞生长因子 21、脂联素与冠状动脉性心脏病的相关性. 中华高血压杂志, 2016, 24(8): 758-762.
31. 郭功亮, 吴金义, 张蕾, 等. 中国成年人血清 FGF21 水平与冠心病风险. 中国老年学杂志, 2015, 3(35): 1233-1235.
32. 颜云宙, 黄伟萍, 陈捷, 等. 老年糖尿病并冠心病患者血清成纤维细胞生长因子 21 与脂联素的检测意义. 中国乡村医药, 2016, 23(5): 64-65.
33. Shen Y, Ma X, Zhou J, et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol, 2013, 12: 124.
34. Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab, 2013, 18(3): 333.
35. Huang J, Ishino T, Chen G, et al. Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther, 2013, 346(2): 270-280.
36. Talukdar S, Zhou Y, Li D, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab, 2016, 23(2): 427-440.
37. Dong JQ, Rossulek M, Somayaji VR, et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 minetic,in a first-in-human study. Rr J Clin Pharmacol, 2015, 80(5): 1051.
38. Videla LA, Fernandez V, Vargas R, et al. Upregulation of rat liver PPARalphaFGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol. Biofactors, 2016, 42(6): 638-646.
39. Lee Y, Lim S, Hong ES, et al. Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol(Oxf), 2014, 80(1): 57-64.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

The research advance of fibroblast growth factor 21 in anti-atherosclerosis

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