LHPP deficiency aggravates liver fibrosis through TGF-β/Smad3 signaling

被引：0

作者：

Zhang, Yue ^{[1
]}

Li, Bi-min ^{[1
]}

Zhang, Wang ^{[2
]}

Chen, Peng ^{[1
]}

Liu, Linxiang ^{[1
]}

Nie, Yuan ^{[1
]}

Huang, Chenkai ^{[1
]}

Zhu, Xuan ^{[1
]}

机构：

[1] Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Jiangxi Med Coll,Digest Dis Hosp, 17 Yongwaizhengjie Rd, Nanchang 330006, Jiangxi, Peoples R China

[2] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Gastroenterol, Hengyang, Peoples R China

来源：

FASEB JOURNAL | 2024年 / 38卷 / 19期

基金：

中国国家自然科学基金;

关键词：

hepatocyte apoptosis; LHPP; liver fibrosis; liver fibrosis model; TGF-beta/Smad3; STEATOHEPATITIS; ACTIVATION; RECEPTORS; DEATH;

D O I：

10.1096/fj.202400117RR

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Liver fibrosis is characterized by a wound-healing response and may progress to liver cirrhosis and even hepatocellular carcinoma. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a tumor suppressor that participates in malignant diseases. However, the role of LHPP in liver fibrosis has not been determined. Herein, the function and regulatory network of LHPP were explored in liver fibrosis. The expression of LHPP in human and murine fibrotic liver tissues was assessed via immunohistochemistry and Western blot analysis. In addition, liver fibrosis was induced in wild-type (WT) and LHPP-/- (KO) mice after carbon tetrachloride (CCl4) or thioacetamide (TAA) treatment. The effect of LHPP was systematically assessed by using specimens acquired from the above murine models. The functional role of LHPP was further explored by detecting the pathway activity of TGF-beta/Smad3 and apoptosis after interfering with LHPP in vitro. To explore whether the function of LHPP depended on the TGF-beta/Smad3 pathway in vivo, an inhibitor of the TGF-beta/Smad3 pathway was used in CCl4-induced WT and KO mice. LHPP expression was downregulated in liver tissue samples from fibrosis patients and fibrotic mice. LHPP deficiency aggravated CCl4- and TAA-induced liver fibrosis. Moreover, through immunoblot analysis, we identified the TGF-beta/Smad3 pathway as a key downstream pathway of LHPP in vivo and in vitro. The effect of LHPP deficiency was reversed by inhibiting the TGF-beta/Smad3 pathway in liver fibrosis. These results revealed that LHPP deficiency exacerbates liver fibrosis through the TGF-beta/Smad3 pathway. LHPP may be a potential therapeutic target in hepatic fibrosis. LHPP inhibits TGF beta/smad3 signaling by suppressing the phosphorylation of smad3 in the hepatocytes, which shows LHPP protects against liver fibrosis.image

引用

页数：9

共 26 条

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