Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

作者全名："Wu, Kang; Liu, Yi; Xia, Jie; Liu, Jiale; Wang, Kai; Liang, Huijun; Xu, Fengli; Liu, Dina; Nie, Dan; Tang, Xin; Huang, Ailong; Chen, Chang; Tang, Ni"

作者地址："[Wu, Kang; Liu, Yi; Xia, Jie; Wang, Kai; Liang, Huijun; Xu, Fengli; Liu, Dina; Nie, Dan; Tang, Xin; Huang, Ailong; Tang, Ni] Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China; [Liu, Jiale; Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China"

通信作者："Huang, AL; Tang, N (通讯作者)，Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China.; Chen, C (通讯作者)，Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:001100741800001

JCR分区：Q1

影响因子：15.1

年份：2024

卷号：11

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：bile acid; early growth response protein 3; hepatic stellate cells; liver fibrosis; solute carrier family 27 member 5

摘要："Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/-) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment. The authors propose a novel mechanism of aberrant bile acid metabolism in liver fibrosis. Loss of solute carrier family 27 member 5 (SLC27A5) accumulates cholic acids (CA) in the liver and promotes hepatic stellate cells activation via early growth response protein 3 (EGR3). Re-expression of SLC27A5 or inhibition of CA levels could be a promising strategy for liver fibrosis treatment.image"

基金机构："The authors thank Dr. T.-C He (University of Chicago, USA) for providing the pAdEasy system. The authors were grateful that Prof. Ding Xue (Tsinghua University, Beijing, China) supplied the CRISPR-Cas9 system. This work was supported by the China National [U20A20392, 82272975, 82072286, 82071671]; China National Natural Science Foundation [D20028]; 111 Project [2023DBXM007]; Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau); Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Kuanren talents program [W0036, W0101]; Future Medical Youth Innovation Team of Chongqing Medical University"

基金资助正文："The authors thank Dr. T.-C He (University of Chicago, USA) for providing the pAdEasy system. The authors were grateful that Prof. Ding Xue (Tsinghua University, Beijing, China) supplied the CRISPR-Cas9 system. This work was supported by the China National Natural Science Foundation (grant no. U20A20392, 82272975, 82072286, 82071671), the 111 Project (No. D20028), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007), Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Kuanren talents program and the DengFeng program of the second affiliated hospital of Chongqing Medical University, and the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101)."