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

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

doi:10.1016/j.celrep.2023.112984

Cited by 4 publications

(5 citation statements)

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“…Among the downregulated pathways, 5-ALA treatment appeared to affect scavenging of heme from plasma, and suppress neutrophil migration and responses to interleukin-1 (IL-1) and macrophage colony-stimulating factor ( Figure S3 A-C). The notion that 5-ALA may mediate hepatic immune responses during HIR is consistent with our recent findings that 5-ALA affects the expression of genes related to immune responses in rat livers following cold storage 7 ( Figure S3 D), and mediates the expression of several chemokine receptors and macrophagic anti-inflammatory (M2-like) polarization in mouse liver partial resection and regeneration models 8 .…”

Section: Resultssupporting

confidence: 90%

“…It can also repress liver injuries and the expression of inflammation- and allograft rejection-related genes, and improve liver metabolism in extendedly cold-stored rat livers following warm reperfusion. Moreover, we also found in donor split liver samples and mouse liver partial resection and regeneration models that 5-ALA synthesis positively correlates with liver regeneration 8 . Interestingly, deficiency of macrophagic heme oxygenase-1 (HO-1/HMOX1), a key enzyme downstream of the 5-ALA metabolic pathway, exacerbates liver inflammation and hepatocellular death in mouse HIR models 9 .…”

Section: Introductionsupporting

confidence: 60%

“…Indeed, we found that 5-ALA treatment could further elevate the expression of Hmox1 in mice following HIR ( Figure S1 C). Nonetheless, the expression of ALAS1 was upregulated in post-transplantation liver samples (Figure 1 A), and higher levels of ALAS1 expression and 5-ALA are associated with better liver recovery following split liver transplantation 8 . These findings demonstrate the importance of upstream 5-ALA metabolic activities in protecting the liver from various types of stress and injuries.…”

Section: Discussionmentioning

confidence: 96%

“…We propose that 5-ALA can modulate the activity of mitochondrial Complex III, alleviate rewarming-induced mitochondrial stress and restore ATP production and redox homeostasis. In patients and mouse liver resection and regeneration models, we unveiled the correlation between 5-ALA synthesis and good liver recovery, and that 5-ALA supplements affect the expression of macrophagic chemokine receptors and M2 polarization 8 . In the context of HIR, the protective role of HO-1 (HMOX1) against organ ischemia-reperfusion injury has been well studied 9 , 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, we found that 5-ALA supplements modulate the macrophagic expression of several chemokine receptors, including C-X3-C Motif Chemokine Receptor 1 (CX3CR1), and promote hepatic recruitment of circulating monocytes/macrophages following liver partial resection and regeneration 8 . Liver resident macrophages, also known as Kupffer cells, are the largest population of the hepatic non-parenchymal cells and crucial for the maintenance of liver immune homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury

Jin,

Guo,

Liu

et al. 2023

Theranostics

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Rationale: Liver resection and transplantation surgeries are accompanied by hepatic ischemia-reperfusion (HIR) injury that hampers the subsequent liver recovery. Given that the liver is the main organ for metabolism and detoxification, ischemia-reperfusion in essence bestows metabolic stress upon the liver and disrupts local metabolic and immune homeostasis. Most of the recent and current research works concerning HIR have been focusing on addressing HIR-induced hepatic injury and inflammation, instead of dealing with the metabolic reprogramming and restoration of redox homeostasis. As our previous work uncovers the importance of 5-aminolevulinate (5-ALA) synthesis during stress adaptation, here we evaluate the effects of supplementing 5-ALA to mitigate HIR injury. Methods: 5-ALA was supplemented into the mice or cultured cells during the ischemic or oxygen-glucose deprivation (OGD) phase. Following reperfusion or reoxygenation, cellular metabolism and energy homeostasis, mitochondrial production of reactive oxygen species (ROS) and transcriptomic changes were evaluated in HIR mouse models or cultured hepatocytes and macrophages. Liver injury, hepatocytic functional tests, and macrophagic M1/M2 polarization were assessed. Results: Dynamic changes in the expression of key enzymes in 5-ALA metabolism were first confirmed in donor and mouse liver samples following HIR. Supplemented 5-ALA modulated mouse hepatic lipid metabolism and reduced ATP production in macrophages following HIR, resulting in elevation of anti-inflammatory M2 polarization. Mechanistically, 5-ALA down-regulates macrophagic chemokine receptor CX3CR1 via the repression of RelA following OGD and reoxygenation (OGD/R). Cx3cr1 KO mice demonstrated milder liver injuries and more macrophage M2 polarization after HIR. M2 macrophage-secreted chitinase-like protein 3 (CHIL3; CHI3L1 in human) is an important HIR-induced effector downstream of CX3CR1 deficiency. Addition of CHIL3/CHI3L1 alone improved hepatocellular metabolism and reduced OGD/R-inflicted injuries in cultured mouse and human hepatocytes. Combined treatment with 5-ALA and CHIL3 during the ischemic phase facilitated lipid metabolism and ATP production in the mouse liver following HIR. Conclusion: Our results reveal that supplementing 5-ALA promotes macrophagic M2 polarization via downregulation of RelA and CX3CR1 in mice following HIR, while M2 macrophage-produced CHIL3/CHI3L1 also manifests beneficial effects to the recovery of hepatic metabolism. 5-ALA and CHIL3/CHI3L1 together mitigate HIR-induced mitochondrial dysfunction and hepatocellular injuries, which may be developed into safe and effective clinical treatments to attenuate HIR injuries.

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Section: Resultssupporting

confidence: 90%

Section: Introductionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 96%