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

• Published in: Cell reports (Cambridge) 2023-08, Vol.42 (8), p.112984-112984, Article 112984
• Main Authors: Chen, Liang, Zhang, Lele, Jin, Guanghui, Liu, Yasong, Guo, Na, Sun, Haobin, Jiang, Yong, Zhang, Xiaomei, He, Guobin, Lv, Guo, Yang, Jinghong, Tu, Xuanjun, Dong, Tao, Liu, Huanyi, An, Jianhong, Si, Ge, Kang, Zhuang, Li, Hua, Yi, Shuhong, Chen, Guihua, Liu, Wei, Yang, Yang, Ou, Jingxing
• Format: Article
• Language: English
• Subjects: 5-aminolevulinate; CP: Immunology; CP: Metabolism; CX3CR1; hepatectomy; hepatocyte proliferation; insulin-like growth factor 1; liver regeneration; liver zonation; macrophage polarization; P53; partial liver transplantation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112984

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. [Display omitted] •The synthesis and level of 5-aminolevulinate (5-ALA) promote liver regeneration•5-ALA affects macrophagic P53 and CX3CR1 functions after partial hepatectomy (PHx)•CX3CR1 deficiency elevates hepatocellular proliferation via IGF-1 signaling in PHx•5-ALA and CX3CR1 antagonists together may aid in PHx or split-liver transplantation Failure in timely liver regeneration and functional recovery threatens the life of patients after partial hepatectomy (PHx) or liver transplantation (PLT). Chen et al. report a 5-aminolevulinate-macrophagic P53/CX3CR1-IGF-1 functional axis that can be targeted to promote liver regeneration without interrupting the normal liver zonation following PHx or PLT.