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TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation

Oncogene (2024)Cite this article

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Abstract

Non-alcoholic steatohepatitis (NASH) is rapidly surpassing viral hepatitis as the primary cause of hepatocellular carcinoma (HCC). However, understanding of NASH-progressed HCC remains poor, which might impede HCC diagnosis and therapy. In this study, we aim to identify shared transcriptional changes between NASH and HCC, of which we focused on E3 ligase TRIM45. We found TRIM45 exacerbates HCC cells proliferation and metastasis in vitro and in vivo. Further transcriptome analysis revealed TRIM45 predominantly affects fatty acid metabolism and oleic acid restored impaired proliferation and metastasis of TRIM45-deficient HCC cells. IP-tandem mass spectrum and FABP5 depriving experiment indicated that TRIM45 enhance fatty acid synthesis depending on FABP5 presence. Interestingly, we found TRIM45 directly added K33-type and K63-type poly-ubiquitin chains to FABP5 NLS domain, which ultimately promoted FABP5 nuclear translocation. Nuclear FABP5 interacted with PPARĪ³ to facilitate downstream lipid synthesis gene expression. We observed TRIM45 accelerated NASH-to-HCC transition and exacerbated both NASH and NASH-HCC with the enhanced fatty acid production in vivo. Moreover, high concentration of fatty acid increased TRIM45 expression. The established mechanism was substantiated by gene expression correlation in TCGA-LIHC. Collectively, our research revealed a common lipid reprograming process in NASH and HCC and identified the cyclical amplification of the TRIM45-FABP5-PPARĪ³-fatty acid axis. This signaling pathway offers potential therapeutic targets for therapeutic intervention in NASH and NASH-progressed HCC.

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Fig. 1: TRIM45 was predicted to be critical in NASH to HCC progression.
Fig. 2: TRIM45 enhances the proliferation and metastasis of HCC cells.
Fig. 3: TRIM45 exacerbates HCC in vivo.
Fig. 4: TRIM45 facilitated HCC proliferation by promoting lipid synthesis.
Fig. 5: TRIM45 increased fatty acids synthesis through interaction with FABP5.
Fig. 6: TRIM45 promoted FABP5 nuclear entry via adding polyubiquitin chains to FABP5 NLS domain.
Fig. 7: FABP5 regulated the expression of fatty acid synthesis genes across PPARĪ³.
Fig. 8: TRIM45 augmented NASH-progressed HCC and lipid synthesis in vivo.

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Data availability

Full data will be available from the corresponding author upon reasonable request. The RNA-sequencing data for this study are deposited in GEO database (GSE261075).

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Acknowledgements

We would like to acknowledge and thank the teachers from the Scientific Research Center of Zhongnan Hospital of Wuhan University for their help in this study.

Funding

This work was supported by Key Research and Development Program of Hubei Province (Grant No. 2021BCA114) and National Natural Science Foundation of China (Grant No. 82300675).

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Author notes

  1. These authors contributed equally: Xiaomian Li, Wenzhi He, Xi Chen.

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China

    Xiaomian Li,Ā Wenzhi He,Ā Xi Chen,Ā Yangwenqing Zhang,Ā Jia Zhang,Ā Fusheng Liu,Ā Jinghua Li,Ā Peng Xia,Ā Weijie Ma,Ā Tiangen Wu,Ā Haitao WangĀ &Ā Yufeng Yuan

  2. Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China

    Xiaomian Li,Ā Wenzhi He,Ā Xi Chen,Ā Yangwenqing Zhang,Ā Jia Zhang,Ā Fusheng Liu,Ā Jinghua Li,Ā Peng Xia,Ā Weijie Ma,Ā Tiangen Wu,Ā Haitao WangĀ &Ā Yufeng Yuan

  3. College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China

    Wenzhi HeĀ &Ā Dongli Zhao

  4. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China

    Yufeng Yuan

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Contributions

XL, WH, XC, TW and YY devised and coordinated the project. WH, XC, TW and YY supervised the project. XL, HW and FL collected clinical HCC samples, XL, FL, JZ, DZ and YZ performed most of the experiments, XL, WH analyzed data. XL, PX, and WM provided significant intellectual input. XL, WH and WM wrote the manuscript with input from all other authors.

Corresponding authors

Correspondence to Tiangen Wu, Haitao Wang or Yufeng Yuan.

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The authors declare no competing interests.

Ethics

The study was conducted in accordance with the principles of the Declaration of Helsinki principles. All animal experiments were approved by the Animal Use and Care Committees at Zhongnan Hospital, Wuhan University (License No. WP20220494). The human samples and data usage was reviewed and approved by the Scientific Research Ethics Committee of Zhongnan Hospital, Wuhan University (License No. 2022076ā€‰K).

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Li, X., He, W., Chen, X. et al. TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation. Oncogene (2024). https://doi.org/10.1038/s41388-024-03056-7

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