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TGF-β Down-regulates Apolipoprotein M Expression through the TAK-1-JNK-c-Jun Pathway in HepG2 Cells

  • Original Article
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Lipids

Abstract

Apolipoprotein M (apoM) is a relatively novel apolipoprotein that plays pivotal roles in many dyslipidemia-associated diseases; however, its regulatory mechanisms are poorly understood. Many cytokines have been identified that down-regulate apoM expression in HepG2 cells, among which transforming growth factor-β (TGF-β) exerts the most potent effects. In addition, c-Jun, a member of the activated protein 1 (AP-1) family whose activity is modulated by c-Jun N-terminal kinase (JNK), decreases apoM expression at the transcriptional level by binding to the regulatory element in the proximal apoM promoter. In this study, we investigated the molecular mechanisms through which TGF-β decreases the apoM level in HepG2 cells. The results revealed that TGF-β inhibited apoM expression at both the mRNA and protein levels in a dose- and time-dependent manner and that it suppressed apoM secretion. These effects were attenuated by treatment of cells with either SP600125 (JNK inhibitor) or c-Jun siRNA. 5Z-7-oxozeaenol [(a TGF-β-activated kinase 1 (TAK-1) inhibitor)] also attenuated the TGF-β-mediated inhibition of apoM expression and suppressed the activation of JNK and c-Jun. These results have demonstrated that TGF-β suppresses apoM expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells.

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Abbreviations

apo:

Apolipoprotein

AP-1:

Activated protein 1

AS:

Atherosclerosis

EGF:

Epidermal growth factor

EMT:

Epithelial-Mesenchymal Transition

ERK1/2:

Extracellular signal-regulated kinase 1/2

HDL:

High-density lipoprotein

HDL-C:

High-density lipoprotein-cholesterol

HGF:

Hepatic growth factor

JNK:

C-Jun N-terminal kinase

LXR:

Liver X receptor

MAP3 K:

Mitogen-activating protein kinase kinase kinase

NO:

Nitric oxide

PI3K:

Phosphatidylinositol 3-kinase

p-JNK:

Phosphorylated JNK

RCT:

Reverse cholesterol transport

RXR:

Retinoid X receptor

S1P:

Sphingosine-1-phosphate

TAK-1:

TGF-β-activated kinase 1

TBS-T:

Tris-buffered saline

T-JNK:

Total JNK

TNF-α:

Tumor necrosis factor alpha

TGF-β:

Transforming growth factor beta

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Acknowledgements

The authors and co-workers gratefully acknowledge research funds provided by the National Natural Science Foundation of China (Nos. 81270360 and 31400652), the Scientific Research Fund of the Hunan Provincial Education Department (13C838), the Science and Technology Planning Project of the Hunan Provincial Science and Technology Department (2014FJ2012), the Natural Science Foundation of Hunan Province (No. 14JJ2084), the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province (2008-244), and the Construct Program of the Key Discipline in Hunan Province, China (Basic Medicine Sciences of University of South China, Xiangjiaofa; No. [2011]76).

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Authors and Affiliations

  1. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, China

    Kun Ren, Zhen-Li Tang, Yue Jiang, Xiao-Shan Peng, Jin-Feng Shi & Guang-Hui Yi

  2. Department of Histology and Embryology, University of South China, Hengyang, 421001, Hunan, China

    Zhong-Cheng Mo & Jin-Feng Shi

  3. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China

    Xing Liu

  4. Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China

    Qing-Hai Zhang

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  1. Kun Ren
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Ren, K., Mo, ZC., Liu, X. et al. TGF-β Down-regulates Apolipoprotein M Expression through the TAK-1-JNK-c-Jun Pathway in HepG2 Cells. Lipids 52, 109–117 (2017). https://doi.org/10.1007/s11745-016-4227-9

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