2. Academic Validation
  3. Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation

Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation

  • J Gastroenterol. 2023 May 7. doi: 10.1007/s00535-023-01996-7.
Man-Ping Ye # 1 2 3,  Wei-Li Lu # 1 2 3,  Qiu-Fan Rao # 1 2 3,  Meng-Jun Li 1 2 3,  Hai-Qin Hong 1 2 3,  Xue-Ying Yang 1 2 3,  Hui Liu 1 2 3,  Jin-Ling Kong 1 2 3,  Ru-Xue Guan 1 2 3,  Yan Huang 1 2 3,  Qing-Hua Hu 4 5,  Fan-Rong Wu 6 7 8
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, People's Republic of China.
  • 2 The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, People's Republic of China.
  • 3 Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, People's Republic of China.
  • 4 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. wufanrong@ahmu.edu.cn.
  • 5 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. wufanrong@ahmu.edu.cn.
  • 6 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, People's Republic of China. wufanrong@ahmu.edu.cn.
  • 7 The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, People's Republic of China. wufanrong@ahmu.edu.cn.
  • 8 Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, People's Republic of China. wufanrong@ahmu.edu.cn.
  • # Contributed equally.
PMID: 37150773 DOI: 10.1007/s00535-023-01996-7
Abstract

Background: The activation of hepatic stellate cells (HSCs) is the key step in the pathogenesis of liver fibrosis, which directly leads to fibrotic pathological changes in the hepatic tissue. Mitochondrial stress exacerbates inflammatory diseases by inducing pathogenic shifts in normal cells. However, the role of mitochondrial stress in HSC activation remains to be elucidated. METHODS: We analyzed the effect of mitochondrial stress on HSC activation. An in vivo hepatic fibrosis model was established by intraperitoneal injection of 40% carbon tetrachloride (CCl4) for 12 weeks. Additionally, using in vitro approach, HSC-T6 cells were treated with 10 ng/mL platelet-derived growth factor-BB (PDGF-BB) for 24 h.

Results: Transcriptional activator 4 (ATF4) is highly expressed in fibrotic liver tissue samples and activated HSCs. We found that AAV8-shRNA-Atf4 alleviated liver fibrosis in rats. ATF4 promoted the activation of HSCs, which was induced by mitochondrial stress. The mechanisms involved ATF4 binding to a specific region of the tribble homologue 3 (TRIB3) promoter. Further, TRIB3 promoted HSCs activation mediated by mitochondrial stress.

Conclusions: ATF4 induces mitochondrial stress by upregulating TRIB3, leading to the activation of HSCs. Therefore, the inhibition of ATF4 during mitochondrial stress may be a promising therapeutic target for liver fibrosis.

Keywords

Hepatic fibrosis; Hepatic stellate cells; Mitochondrial stress; Transcriptional activator 4; Tribble homolog 3.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z