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Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells

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Abstract

Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.

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Abbreviations

HSC:

Hepatic stellate cells

α-SMA:

α-Smooth muscle actin

CO-I:

Type I collagen

ECM:

Extracellular matrix

IR:

Insulin resistance

IBMX:

3-Isobutyl-1-methylxanthine

IRS1:

Insulin receptor substrate

CHOP:

C/EBP homologous protein

GRP78:

Glucose-regulated protein

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

PERK:

PKR-like ER kinase

eIF2α:

Eukaryotic initiation factor 2α

ER:

Endoplasmic reticulum

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Funding

This study was funded by China Postdoctoral Science Foundation (NO. 2018M640611), Shandong Provincial Natural Science Foundation (NO. ZR2019BD026), Shandong Provincial postdoctoral innovation Foundation (No. 201902036) and Affiliated Hospital of Qingdao University Youth Foundation (NO.3104).

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Authors and Affiliations

  1. Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Yingjuan Liu, Xiaolin Wu, Yue Wang & Yunliang Guo

  2. Medical College, Qingdao University, Qingdao, 266071, China

    Yingjuan Liu & Yunliang Guo

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  1. Yingjuan Liu
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  2. Xiaolin Wu
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  3. Yue Wang
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Contributions

Conceptualization, Y.L.; methodology, X.L. and Y.L.; software, Y.W.;data curation, X.L. and Y.L.; writing—original draft preparation, Y.L.; writing—review and editing, Y.G. and Y.L.; funding acquisition, Y.L. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yunliang Guo.

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Liu, Y., Wu, X., Wang, Y. et al. Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells. Mol Cell Biochem 476, 2527–2538 (2021). https://doi.org/10.1007/s11010-020-03990-6

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