Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this...

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Autores principales:	Yudi Zhang, Yuping Fu, Tiannan Jiang, Binghua Liu, Hongke Sun, Ying Zhang, Boyuan Fan, Xiaoli Li, Xinghua Qin, Qiangsun Zheng
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	atrial fibrillation obesity fatty acids oxidation lipotoxicity l-carnitine AMPK (5′-AMP activated kinase) Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/abe7ed0a1ed043b0b9513ee0d2ab6881
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spelling	oai:doaj.org-article:abe7ed0a1ed043b0b9513ee0d2ab68812021-12-01T08:10:32ZEnhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity1663-981210.3389/fphar.2021.771940https://doaj.org/article/abe7ed0a1ed043b0b9513ee0d2ab68812021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.771940/fullhttps://doaj.org/toc/1663-9812Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.Yudi ZhangYuping FuTiannan JiangBinghua LiuHongke SunYing ZhangBoyuan FanXiaoli LiXinghua QinQiangsun ZhengFrontiers Media S.A.articleatrial fibrillationobesityfatty acids oxidationlipotoxicityl-carnitineAMPK (5′-AMP activated kinase)Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	atrial fibrillation obesity fatty acids oxidation lipotoxicity l-carnitine AMPK (5′-AMP activated kinase) Therapeutics. Pharmacology RM1-950
spellingShingle	atrial fibrillation obesity fatty acids oxidation lipotoxicity l-carnitine AMPK (5′-AMP activated kinase) Therapeutics. Pharmacology RM1-950 Yudi Zhang Yuping Fu Tiannan Jiang Binghua Liu Hongke Sun Ying Zhang Boyuan Fan Xiaoli Li Xinghua Qin Qiangsun Zheng Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
description	Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.
format	article
author	Yudi Zhang Yuping Fu Tiannan Jiang Binghua Liu Hongke Sun Ying Zhang Boyuan Fan Xiaoli Li Xinghua Qin Qiangsun Zheng
author_facet	Yudi Zhang Yuping Fu Tiannan Jiang Binghua Liu Hongke Sun Ying Zhang Boyuan Fan Xiaoli Li Xinghua Qin Qiangsun Zheng
author_sort	Yudi Zhang
title	Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
title_short	Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
title_full	Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
title_fullStr	Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
title_full_unstemmed	Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
title_sort	enhancing fatty acids oxidation via l-carnitine attenuates obesity-related atrial fibrillation and structural remodeling by activating ampk signaling and alleviating cardiac lipotoxicity
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/abe7ed0a1ed043b0b9513ee0d2ab6881
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Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity

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