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Inflammation

pp 1–13 | Cite as

Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 Ameliorates Liver Fibrosis via Mitigation of Intestinal Endotoxemia

  • Yanting Zou
  • Shuyu Li
  • Beili Xu
  • Hongying Guo
  • Shuncai Zhang
  • Yu CaiEmail author
Original Article

Abstract

Lipopolysaccharide (LPS) is demonstrated to cause “two-hit” injury to liver. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in LPS clearance. Hepatocyte nuclear factor-1 alpha (HNF-1α) and sterol regulatory element-binding protein 2 (SREBP2) were reported to be responsible for PCSK9 gene transcription and regulation. We aim to clarify the expression status of PCSK9 during the process of liver fibrosis and to verify the effect on liver fibrosis via PCSK9 inhibition. In this study, we found that PCSK9 increased significantly in human and BDL mouse injured liver tissues, so did HNF-1α and SREBP2. No significant difference of plasma PCSK9 was observed. Inhibited PCSK9 using CRISPR-PCSK9 adeno-associated virus in BDL mice ameliorated liver inflammation and fibrosis, with LPS decrease in serum, without any change in intestinal wall integrity. PCSK9 expression of L02 hepatocytes can be induced by LPS; however, they lose the ability at high content of LPS. L02 cells increased LPS uptake after PCSK9 knockout. Taken together, these results suggest that, with PCSK9 increasing during liver fibrosis advancement, its inhibition can ameliorate liver injury by enhancing LPS uptake in hepatocytes; however, the enhancement is limited for destruction to hepatocytes by high LPS.

KEY WORDS

proprotein convertase subtilisin/kexin type 9 intestinal endotoxemia liver fibrosis hepatocyte lipopolysaccharide 

Abbreviations

PCSK9

proprotein convertase subtilisin/kexin type 9

BDL

bile duct ligation

HNF-1α

hepatocyte nuclear factor-1 alpha

SREBP2

sterol regulatory element-binding protein 2

qRT-PCR

real-time quantitative polymerase chain reaction

LPS

lipopolysaccharide

ELISA

enzyme-linked immunosorbent assay

FITC

fluorescein isothiocyanate

TNF-α

tumor necrosis factor-α

LDLR

low density lipoprotein receptor

LDL

low density lipoprotein

VLDL

very-low-density lipoproteins

H&E

hematoxylin-eosin stain

ALT

alanine transaminase

AST

aspartate transaminase

DMEM

Dulbecco’s modified Eagle’s medium

FBS

fetal bovine serum

CHB

chronic hepatitis B

AIH

auto-immunological hepatitis

PBC

primary biliary cholangitis

ALD

alcoholic liver disease

Notes

Funding

This research was funded by the Science and Technology Commission of Shanghai Municipality, grant number 16411952300 and 19ZR1409400, and Zhongshan Hospital, Fudan University, grant number 2019ZSQN25.

Compliance with Ethical Standards

The whole experiment was performed in accordance with the guiding principles for the care and use of laboratory animals approved by the Research Ethics Committee of Zhongshan Hospital, Fudan University (No. 2016-156).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yanting Zou
    • 1
  • Shuyu Li
    • 1
  • Beili Xu
    • 1
  • Hongying Guo
    • 2
  • Shuncai Zhang
    • 1
  • Yu Cai
    • 1
    Email author
  1. 1.Department of Gastroenterology and Hepatology, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Severe Hepatitis, Shanghai Public Health Clinical CenterFudan UniversityShanghaiPeople’s Republic of China

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