Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 Ameliorates Liver Fibrosis via Mitigation of Intestinal Endotoxemia
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 WORDSproprotein convertase subtilisin/kexin type 9 intestinal endotoxemia liver fibrosis hepatocyte lipopolysaccharide
proprotein convertase subtilisin/kexin type 9
bile duct ligation
hepatocyte nuclear factor-1 alpha
sterol regulatory element-binding protein 2
real-time quantitative polymerase chain reaction
enzyme-linked immunosorbent assay
tumor necrosis factor-α
low density lipoprotein receptor
low density lipoprotein
Dulbecco’s modified Eagle’s medium
fetal bovine serum
chronic hepatitis B
primary biliary cholangitis
alcoholic liver disease
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.
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