Phosphatidylethanolamine-binding protein 4 deficiency exacerbates carbon tetrachloride-induced liver fibrosis by regulating the NF-κB signaling pathway

Abstract

Liver fibrosis is a pathological process which can progress to hepatocirrhosis, even hepatocellular carcinoma. Phosphatidylethanolamine-binding protein 4 (PEBP4) is a secreted protein involved in regulating many molecular pathways, whereas its roles in diseases including hepatic fibrosis remain undefined. The nuclear factor-κappa B (NF-κB) signaling pathway has been found to be involved in the development of liver fibrosis. In this study, we generated a hepatocyte-conditional knockout (CKO) mouse model of PEBP4, and explored the potential functions of PEBP4 on liver fibrosis and the NF-κB signaling pathway in a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. We demonstrated that PEBP4 CKO aggravated CCl4-triggered liver fibrosis, as evidenced by altered histopathology, an increase in the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hydroxyproline (HYP) levels, and more collagen deposition, as well as by enhanced expression of fibrotic markers including α-smooth muscle actin (α-SMA), collagen I and collagen III. Mechanistically, PEBP4 deficiency activated the NF-κB signaling pathway, as indicated by increased phosphorylation of NF-κB p65 and inhibitor protein κB inhibitor-α (IκB-α), and nuclear NF-κB p65 expression in the fibrotic liver. Notably, the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) partially blocked the activation of the NF-κB pathway, and reversed the pro-fibrotic effect of PEBP4 deletion in CCl4-treated mice. Together, these results suggest that PEBP4 deficiency results in aggravation of liver fibrosis and activation of the NF-κB signaling pathway, supporting a novel concept that PEBP4 is a crucial player in hepatic fibrosis, but also might be a negative regulator of the NF-κB signaling in liver fibrosis.

Potential of PAQosome as a therapeutic target for hepatic fibrosis

“…This indicated that ASDURF may be a regulator of TGF-β1/Smad3 and NF-κB signaling pathways, and TGF-β1/Smad3 and NF-κB are important pathways in hepatic fibrosis. [3][4][5] This further supports the hypothesis that ASDURF is involved in managing hepatic fibrosis. The dual-luciferase test revealed that ASDURF enhanced ASNSD1 promoter activity, and Co-IP demonstrated that ASDURF could attach to ASNSD1 (Fig.…”

“…P‐smad3 and p‐p65 were downregulated after ASDURF interference in LX‐2 cell lines. This indicated that ASDURF may be a regulator of TGF‐β1/Smad3 and NF‐κB signaling pathways, and TGF‐β1/Smad3 and NF‐κB are important pathways in hepatic fibrosis 3–5 . This further supports the hypothesis that ASDURF is involved in managing hepatic fibrosis.…”

“…2,3 Additionally, NF-κB controls hepatic fibrogenesis. 4,5 Furthermore, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is linked to HSC activation, proliferation, and extracellular matrix production according to a number of studies. 6,7 This was used as the backdrop to explore the function of the PAQosome in hepatic fibrosis.…”

“…The most traditional method for activating HSCs is through the transforming growth factor‐β1 (TGFβ1)/ Sekelsky mothers against decapentaplegic homologue 3 (Smad3) signaling pathway 2,3 . Additionally, NF‐κB controls hepatic fibrogenesis 4,5 . Furthermore, the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is linked to HSC activation, proliferation, and extracellular matrix production according to a number of studies 6,7 .…”

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

“…PEBP4 has been reported to have anti-apoptotic function and is associated with the occurrence and development of various tumors [ 10 ]. In addition, PEBP4 is closely related to acute liver injury and liver fibrosis on account of its anti-inflammatory and liver-protective effects [ 11 , 12 ]. PEBP4 has been also identified as a new-found marker of type II AECs [ 13 ], whose dysfunction is involved in the occurrence and progression of ALI.…”