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Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity
Yunlan Li1,2, Xinxin Liu3, Lin Niu4
1School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China. liyunlanrr@163.com.
Abstract:
A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.
Insights
This study reveals how organotin DBDCT impacts liver cells, identifying key proteins involved in the PPAR signaling pathway. DBDCT may modulate PPAR-λ, affecting downstream genes like CD36 and FABP4.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) exhibits significant antitumor activity.
- The precise antitumor and toxic mechanisms of DBDCT remain unclear.
- Understanding DBDCT's molecular targets is crucial for its therapeutic development.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying DBDCT's antitumor and toxic effects.
- To identify hepatic proteins and signaling pathways affected by DBDCT treatment.
- To investigate the role of the peroxisome proliferator-activated receptor (PPAR) signaling pathway in DBDCT's action.
Main Methods:
- Proteomic analysis of hepatic proteins from DBDCT-treated rats using LC-MS/MS with label-free quantitative technology.
- Quantitative analysis of protein and mRNA expression levels.
- Utilizing a PPAR-λ blocking agent (T0070907) to assess pathway modulation.
Main Results:
- 149 differentially expressed proteins were identified in DBDCT-treated rat liver cells.
- Five proteins and mRNAs (CD36, FABP4, EHHADH, ACAA1, PEPCK) involved in the PPAR signaling pathway were identified.
- Both PPAR-α and PPAR-λ levels were significantly decreased at protein and mRNA levels.
- DBDCT was found to up-regulate CD36, FABP4, and EHHADH via PPAR-λ modulation.
Conclusions:
- DBDCT's mechanism involves the modulation of the PPAR signaling pathway, particularly PPAR-λ.
- DBDCT influences the expression of key genes such as CD36, FABP4, and EHHADH.
- These findings provide insights into DBDCT's antitumor activity and potential toxicity, guiding future research and drug development.
