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Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart.
Cell Death Dis. 2018 02 14; 9(2):227.CD

Abstract

Our previous studies showed that both exogenous and endogenous FGF21 inhibited cardiac apoptosis at the early stage of type 1 diabetes. Whether FGF21 induces preventive effect on type 2 diabetes-induced cardiomyopathy was investigated in the present study. High-fat-diet/streptozotocin-induced type 2 diabetes was established in both wild-type (WT) and FGF21-knockout (FGF21-KO) mice followed by treating with FGF21 for 4 months. Diabetic cardiomyopathy (DCM) was diagnosed by significant cardiac dysfunction, remodeling, and cardiac lipid accumulation associated with increased apoptosis, inflammation, and oxidative stress, which was aggravated in FGF21-KO mice. However, the cardiac damage above was prevented by administration of FGF21. Further studies demonstrated that the metabolic regulating effect of FGF21 is not enough, contributing to FGF21-induced significant cardiac protection under diabetic conditions. Therefore, other protective mechanisms must exist. The in vivo cardiac damage was mimicked in primary neonatal or adult mouse cardiomyocytes treated with HG/Pal, which was inhibited by FGF21 treatment. Knockdown of AMPKα1/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG/Pal partially via upregulating AMPK-AKT2-NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid β-oxidation via inhibition of ACC-CPT-1 pathway. And, inhibition of fatty acid β-oxidation partially blocked FGF21-induced protection in cardiomyocytes. Further, in vitro and in vivo studies indicated that FGF21-induced cardiac protection against type 2 diabetes was mainly attributed to lipotoxicity rather than glucose toxicity. These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK-AKT2-NRF2-mediated antioxidative pathway and AMPK-ACC-CPT-1-mediated lipid-lowering effect in the heart.

Authors+Show Affiliations

Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China. Wenzhou Biomedical Innovation Center, Wenzhou, China.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China. Wenzhou Biomedical Innovation Center, Wenzhou, China.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. lu89118@medmail.com.cn.Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. zhangchi515@126.com. Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China. zhangchi515@126.com. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China. zhangchi515@126.com. Wenzhou Biomedical Innovation Center, Wenzhou, China. zhangchi515@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29445083

Citation

Yang, Hong, et al. "Fibroblast Growth Factor-21 Prevents Diabetic Cardiomyopathy Via AMPK-mediated Antioxidation and Lipid-lowering Effects in the Heart." Cell Death & Disease, vol. 9, no. 2, 2018, p. 227.
Yang H, Feng A, Lin S, et al. Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis. 2018;9(2):227.
Yang, H., Feng, A., Lin, S., Yu, L., Lin, X., Yan, X., Lu, X., & Zhang, C. (2018). Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death & Disease, 9(2), 227. https://doi.org/10.1038/s41419-018-0307-5
Yang H, et al. Fibroblast Growth Factor-21 Prevents Diabetic Cardiomyopathy Via AMPK-mediated Antioxidation and Lipid-lowering Effects in the Heart. Cell Death Dis. 2018 02 14;9(2):227. PubMed PMID: 29445083.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. AU - Yang,Hong, AU - Feng,Anyun, AU - Lin,Sundong, AU - Yu,Lechu, AU - Lin,Xiufei, AU - Yan,Xiaoqing, AU - Lu,Xuemian, AU - Zhang,Chi, Y1 - 2018/02/14/ PY - 2017/09/07/received PY - 2018/01/04/accepted PY - 2017/12/29/revised PY - 2018/2/16/entrez PY - 2018/2/16/pubmed PY - 2019/9/12/medline SP - 227 EP - 227 JF - Cell death & disease JO - Cell Death Dis VL - 9 IS - 2 N2 - Our previous studies showed that both exogenous and endogenous FGF21 inhibited cardiac apoptosis at the early stage of type 1 diabetes. Whether FGF21 induces preventive effect on type 2 diabetes-induced cardiomyopathy was investigated in the present study. High-fat-diet/streptozotocin-induced type 2 diabetes was established in both wild-type (WT) and FGF21-knockout (FGF21-KO) mice followed by treating with FGF21 for 4 months. Diabetic cardiomyopathy (DCM) was diagnosed by significant cardiac dysfunction, remodeling, and cardiac lipid accumulation associated with increased apoptosis, inflammation, and oxidative stress, which was aggravated in FGF21-KO mice. However, the cardiac damage above was prevented by administration of FGF21. Further studies demonstrated that the metabolic regulating effect of FGF21 is not enough, contributing to FGF21-induced significant cardiac protection under diabetic conditions. Therefore, other protective mechanisms must exist. The in vivo cardiac damage was mimicked in primary neonatal or adult mouse cardiomyocytes treated with HG/Pal, which was inhibited by FGF21 treatment. Knockdown of AMPKα1/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG/Pal partially via upregulating AMPK-AKT2-NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid β-oxidation via inhibition of ACC-CPT-1 pathway. And, inhibition of fatty acid β-oxidation partially blocked FGF21-induced protection in cardiomyocytes. Further, in vitro and in vivo studies indicated that FGF21-induced cardiac protection against type 2 diabetes was mainly attributed to lipotoxicity rather than glucose toxicity. These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK-AKT2-NRF2-mediated antioxidative pathway and AMPK-ACC-CPT-1-mediated lipid-lowering effect in the heart. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/29445083/Fibroblast_growth_factor_21_prevents_diabetic_cardiomyopathy_via_AMPK_mediated_antioxidation_and_lipid_lowering_effects_in_the_heart_ L2 - https://doi.org/10.1038/s41419-018-0307-5 DB - PRIME DP - Unbound Medicine ER -