Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling

  • Cell Rep. 2023 Aug 13;42(8):112984. doi: 10.1016/j.celrep.2023.112984.
Liang Chen  1 ,  Lele Zhang  2 ,  Guanghui Jin  2 ,  Yasong Liu  2 ,  Na Guo  3 ,  Haobin Sun  2 ,  Yong Jiang  2 ,  Xiaomei Zhang  2 ,  Guobin He  4 ,  Guo Lv  4 ,  Jinghong Yang  2 ,  Xuanjun Tu  4 ,  Tao Dong  2 ,  Huanyi Liu  4 ,  Jianhong An  5 ,  Ge Si  6 ,  Zhuang Kang  6 ,  Hua Li  2 ,  Shuhong Yi  2 ,  Guihua Chen  1 ,  Wei Liu  7 ,  Yang Yang  8 ,  Jingxing Ou  9
Affiliations
  • 1. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University; Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University; Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3. Department of Anesthesiology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4. Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5. School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China.
  • 6. Department of Radiology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 7. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University; Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 8. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University; Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 9. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University; Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 37578861 DOI: 10.1016/j.celrep.2023.112984
Abstract

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, Chemokine Receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

Keywords
5-aminolevulinate; CP: Immunology; CP: Metabolism; CX3CR1; P53; hepatectomy; hepatocyte proliferation; insulin-like growth factor 1; liver regeneration; liver zonation; macrophage polarization; partial liver transplantation.
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