The high-fat diet induces myocardial fibrosis in the metabolically healthy obese minipigs—The role of ER stress and oxidative stress

Li, Sin‐Jin; Liu, Chia-Hsin; Chu, Hsien-Pin; Mersmann, Harry J.; Ding, Shih‐Torng; Chu, Chun-Han; Wang, Chia-Yu; Chen, Ching‐Yi

doi:10.1016/j.clnu.2016.06.002

Cited by 28 publications

(21 citation statements)

References 34 publications

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“…Unoxidized FAs in cardiac myocytes could produce oxidative stress and ER stress, resulting in lipotoxicty . Oxidative stress and ER stress‐initiated apoptotic signalling pathway play crucial roles in the pathogenesis of obesity‐induced cardiac abnormality …”

Section: Introductionmentioning

confidence: 99%

“…5,6 Oxidative stress and ER stress-initiated apoptotic signalling pathway play crucial roles in the pathogenesis of obesity-induced cardiac abnormality. [7][8][9] AMP-activated protein kinase (AMPK) is a major cellular sensor of energy balance in mammalian cells. 10 Liver kinase B1 (LKB1) can act as major upstream kinases of AMPK and phosphorylate AMPK at Thr172.…”

Section: Introductionmentioning

confidence: 99%

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CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

Zuo

Zhao

et al. 2020

J Cellular Molecular Medi

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CTRP9 has been reported to regulate lipid metabolism and exert cardioprotective effects, yet its role in high‐fat diet (HFD)‐induced cardiac lipotoxicity and the underlying mechanisms remain unclear. In the current study, we established HFD‐induced obesity model in wild‐type (WT) or CTRP9 knockout (CTRP9‐KO) mice and palmitate‐induced lipotoxicity model in neonatal rat cardiac myocytes (NRCMs) to investigate the effects of CTRP9 on cardiac lipotoxicity. Our results demonstrated that the HFD‐fed CTRP9‐KO mice accentuated cardiac hypertrophy, fibrosis, endoplasmic reticulum (ER) stress‐initiated apoptosis and oxidative stress compared with the HFD‐fed WT mice. In vitro, CTRP9 treatment markedly alleviated palmitate‐induced oxidative stress and ER stress‐induced apoptosis in NRCMs in a dose‐dependent manner. Phosphorylated AMPK at Thr172 was reduced, and phosphorylated mammalian target of rapamycin (mTOR) was strengthened in the heart of the HFD‐fed CTRP9‐KO mice compared with the HFD‐fed control mice. In vitro, AMPK inhibitor compound C significantly abolished the effects of CTRP9 on the inhibition of the apoptotic pathway in palmitate‐treated NRCMs. In a further mechanistic study, CTRP9 enhanced expression of phosphorylated LKB1 at Ser428 and promoted LKB1 cytoplasmic localization. Besides, silencing of LKB1 gene by lentivirus significantly prohibited activation of AMPK by CTRP9 and partially eliminated the protective effect of CTRP9 on the cardiac lipotoxicity. These results indicate that CTRP9 exerted anti‐myocardial lipotoxicity properties and inhibited cardiac hypertrophy probably through the LKB1/AMPK signalling pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

Zuo

Zhao

et al. 2020

J Cellular Molecular Medi

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“…This obese minipig exhibits the metabolic syndrome (which includes hypertension, hyperglycaemia, abdominal obesity, and dyslipidaemia) and fatty liver; furthermore, the endoplasmic reticulum stress, autophagy and lipotoxicity participate in the pathological mechanism of cardiomyopathy. 18,19 Our latest study finds that pericardial adipose tissue (PAT) is involved in the cardiac fibrosis of HFD-fed pigs. The secretomes of PAT impaired mitochondrial functions and caused cardiomyocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The impact of DRP1 on myocardial fibrosis in the obese minipig

Chen

Wang

et al. 2020

Eur J Clin Investigation

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Background The heart is a highly oxidative tissue, thus mitochondria play a major role in maintaining optimal cardiac function. Our previous study established a dietary‐induced obese minipig with cardiac fibrosis. The aim of this study was to elucidate the role of mitochondrial dynamics in cardiac fibrosis of obese minipigs. Design Four‐month‐old Lee‐Sung minipigs were randomly divided into two groups: a control group (C) and an obese group (O) by feeding a control diet or a high‐fat diet (HFD) for 6 months. Exposure of H9c2 cardiomyoblasts to palmitate was used to explore the effects of high‐fat on induction of myocardial injury in vitro. Results The O pigs displayed greater heart weight and cardiac collagen accumulation. Obese pigs exhibited a lower antioxidant capacity, ATP concentration, and higher oxidative stress in the left ventricle (LV). The HFD caused downregulation in protein expression of PGC‐1α and OPA1, and upregulation of DRP1, FIS1, and PINK1 in the LV of O compared to C pigs. Furthermore, palmitate induced apoptosis and decreased ATP content in H9c2 cells. Palmitate elevated the protein expression of DRP1 and PINK1 in these cells. Inhibition of DRP1 protein expression by siDRP1 in H9c2 cells resulted in enhanced ATP and decreased palmitate‐induced apoptosis. Conclusions These results suggest that mitochondrial dynamics were linked to the progression of obesity‐related cardiac injury. Inhibition of DRP1 after palmitate exposure in H9c2 cells resulted in improved ATP level and decreased apoptosis in vitro suggesting that mitochondrial fission serves a key role in progression of obesity‐induced cardiac fibrosis.

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“…11 Endoplasmic reticulum (ER) stress, autophagy and lipotoxicity participate in the pathological mechanisms of obesityrelated cardiac fibrosis. 11 Endoplasmic reticulum (ER) stress, autophagy and lipotoxicity participate in the pathological mechanisms of obesityrelated cardiac fibrosis.…”

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confidence: 99%

“…We previously established a dietary-induced obese minipig model and found that a high-fat diet (HFD) induces metabolic dysfunctions and myocardial fibrosis. 11 Endoplasmic reticulum (ER) stress, autophagy and lipotoxicity participate in the pathological mechanisms of obesityrelated cardiac fibrosis. In addition, we found greater PAT accumulation around the heart of these obese minipigs.…”

mentioning

confidence: 99%