The role of FGF21 in the pathogenesis of cardiovascular disease

Zhang, Ying; Liú, Dan; Long, Xiaoxue; Fang, Qichen; Jia, Weiping; Li, Huating

doi:10.1097/cm9.0000000000001890

Cited by 29 publications

(18 citation statements)

References 147 publications

(347 reference statements)

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“…In the cardiovascular system, FGF21 exerts a protective function on endothelial cells by resisting oxidative stress, inhibiting aberrant vascular remodeling, and antagonizing angiotensin II [ 47 , 48 , 49 , 50 ]. Studies have demonstrated that FGF21 can also significantly reduce fasting blood glucose level and improve glucose clearance without hypoglycemia [ 51 , 52 , 53 , 54 ]. Significant FGF21 production in the liver and enhanced circulating FGF21 may, therefore, contribute to the beneficial effects of PEM.…”

Section: Discussionmentioning

confidence: 99%

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

et al. 2022

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Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

et al. 2022

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“…FGF21 can induce cardiac protection by preventing cardiac lipotoxicity, oxidative stress, and inflammation by directly binding to the FGFR of the heart [222]. However, in another multiethnic clinical study, FGF21 was not a CVD biomarker in atherosclerosis patients without known CVD [44].…”

Section: Fgf21: As a Biomarker For Metabolic And Cardiovascular Diseasesmentioning

confidence: 95%

“…In addition, mechanistic studies revealed that FGF21 can act directly on the cardiovascular system and may be used as an early biomarker of CVD. FGF21 can induce cardiac protection by preventing cardiac lipotoxicity, oxidative stress, and inflammation by directly binding to the FGFR of the heart 222 . However, in another multiethnic clinical study, FGF21 was not a CVD biomarker in atherosclerosis patients without known CVD 44 .…”

Section: Summary Of Fgf21 In Cvmdmentioning

confidence: 99%

Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine

Tan¹,

Tong²,

Chen³

et al. 2023

Int. J. Biol. Sci.

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Cardiovascular and metabolic disease (CVMD) is becoming increasingly prevalent in developed and developing countries with high morbidity and mortality. In recent years, fibroblast growth factor 21 (FGF21) has attracted intensive research interest due to its purported role as a potential biomarker and critical player in CVMDs, including atherosclerosis, coronary artery disease, myocardial infarction, hypoxia/reoxygenation injury, heart failure, type 2 diabetes, obesity, and nonalcoholic steatohepatitis. This review summarizes the recent developments in investigating the role of FGF21 in CVMDs and explores the mechanism whereby FGF21 regulates the development of CVMDs. Novel molecular targets and related pathways of FGF21 (adenosine 5'-monophosphate-activated protein kinase, silent information regulator 1, autophagy-related molecules, and gut microbiota-related molecules) are highlighted in this review. Considering the poor pharmacokinetics and biophysical properties of native FGF21, the development of new generations of FGF21-based drugs has tremendous therapeutic potential. Related preclinical and clinical studies are also summarized in this review to foster clinical translation. Thus, our review provides a timely and insightful overview of the physiology, biomarker potential, molecular targets, and therapeutic potential of FGF21 in CVMDs.

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“…When FGF binds to its receptors, it mediates intracellular signaling through four pathways: RAS/RAF/mitogen-activation protein kinase (MAPK) signaling pathway, phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase AKT signaling pathway, signal transducer and activator of transcription (STAT) signaling pathway, and phosphoinositide phospholipase C (PLC) γ signaling pathway ( 78 , 79 ). FGF21 contains 209 and 210 amino acid residues in humans and rodents, respectively; it consists 13 N-terminal residues and 40 C-terminal residues and the gene encoding FGF21 is located on chromosome 19 ( 80 ). The activation of the FGFR1 receptor by FGF21 requires the involvement of the cofactor β-klotho ( 81 ).…”

Section: Myokines and Dnmentioning

confidence: 99%

Myokines: Novel therapeutic targets for diabetic nephropathy

Yang

Luo²,

Yang³

et al. 2022

Front. Endocrinol.

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With the increasing incidence of diabetic nephropathy (DN), there is an urgent need to find effective DN preventive and therapeutic modalities. It is widely believed that effective exercise is good for health. However, the beneficial role of exercise in kidney disease, especially in DN, and the underlying molecular mechanisms have rarely been reported. Muscle is not only an important motor organ but also an important endocrine organ, secreting a group of proteins called “myokines” into the blood circulation. Circulating myokines then move to various target organs to play different biological roles. In this review, we summarize the currently known myokines and the progress in research relating them to DN and discuss its potential as a therapeutic target for DN.

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The role of FGF21 in the pathogenesis of cardiovascular disease

Cited by 29 publications

References 147 publications

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine

Myokines: Novel therapeutic targets for diabetic nephropathy

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