Role of B Cell Lymphoma 2 in the Regulation of Liver Fibrosis in miR-122 Knockout Mice.

Kun-Yu Teng,Kalpana Ghoshal,Samson T Jacob,Juan M Barajas,Peng Hu

doi:10.3390/biology9070157

Kun-Yu Teng, Kalpana Ghoshal + Show 3 more

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https://doi.org/10.3390/biology9070157

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Abstract

MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.

Highlights

MicroRNAs are ~21–25 nucleotide non-coding RNAs that post-transcriptionally regulate gene expression in mammals [1,2]
We found that B-cell lymphoma 2 (BCL2) expression was negatively regulated by miR-122 through c-MYC, which we previously showed to be indirectly suppressed by miR-122 through targeting the transcriptional activator (E2F1) and co-activator (TFDP2) in mouse hepatic cells [37]
We found that Venetoclax suppressed cell proliferation and fibrogenic gene expression in the human-liver-derived stellate cell line (LX-2)

Summary

Introduction

MicroRNAs are ~21–25 nucleotide non-coding RNAs that post-transcriptionally regulate gene expression in mammals [1,2]. It is widely accepted that the hepatic stellate cells (HSCs) are the main collagen-producing cells during liver fibrosis [16,18,19]. When the liver is injured, damaged hepatocytes release TGFβ1 and ROS, while Kupffer cells release TNF-α and TGFβ1 to activate quiescent HSCs into myofibroblast-like cells [16,20,21,22,23]. If the damage persists for an extended period of time, the dead hepatic cells are replaced by fibrotic tissue, which increases the stiffness of the liver and leads to cirrhosis [25,26]. The expression of miR-122 was drastically decreased in a mouse liver fibrosis model induced by carbon tetrachloride (CCl4) [27]. Several studies have shown that the circulating microRNAs could be used as biomarkers for various liver disease, including cirrhosis (reviewed in [28])

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