IDDF2023-ABS-0258 Decipher the mitochondrial reprogramming in dysregulated immunometabolism during steatotic liver graft injury
Year: 2023
Type: conference-paper
Abstract: Background The polarization of M1 macrophage facilitates steatotic liver graft injury and is regulated by metabolic reprogramming. We previously demonstrated that compromised PGC1α signaling mediated steatotic graft injury by dysregulating mitochondrial function (Liu et al., Ann Surg. 2022). Hence, this study aims to elucidate the role of PGC1α in M1 macrophage-mediated steatotic graft injury regarding the mechanism of mitochondrial metabolic reprogramming. Methods The PGC1α transcriptional level and its association with steatotic graft dysfunction were explored in a liver transplant clinical cohort. Macrophage phenotype in terms of PGC1α expression pattern was investigated in a rat orthotopic liver transplant model. The mechanism of PGC1α in macrophage polarization and its mitochondrial metabolic reprogramming, as well as in graft injury was studied in a mouse model with hepatic ischemia and reperfusion. Results The PGC1α transcriptional level was indicative of liver steatosis, and the cutoff was determined by the ROC curve with an AUC of 0.811 (p<0.001) (IDDF2023-ABS-0258 Figure 1A). Moreover, the steatotic graft recipients with lower PGC1α levels showed significantly elevated ALT and deteriorated long-term graft survival (IDDF2023-ABS-0258 Figure 1B-C). In the steatotic graft of the rat model, oxidative phosphorylation (OXPHOS) was downregulated, but glycolysis was enhanced, which was indicated by decreased complex II activity and increased plasma lactate concentration (IDDF2023-ABS-0258 Figure 1D). In addition, the intrahepatic M1 macrophage polarization was increased and was CD68+IFNγ+PGC1αlow dominant (IDDF2023-ABS-0258 Figure 1E). Mechanistically, inhibiting PGC1α in the mouse model down-regulated OXPHOS and increased M1 macrophage, whereas reactivation of PGC1α restored OXPHOS activity and reduced M1 population (IDDF2023-ABS-0258 Figure 1F-G). Phenotypically, PGC1α inhibition resulted in elevated ALT, exacerbated portal triad inflammation, and deteriorated steatosis, whereas PGC1α reactivation attenuated these phenomena (IDDF2023-ABS-0258 Figure 1H-I). Conclusions Compromised PGC1α signaling drives steatotic liver graft injury via promoting M1 macrophage polarization through mitochondrial metabolic reprogramming. Reference Liu J, Pang L, Ng KTP, et al. Compromised AMPK-PGC1alpha Axis Exacerbated Steatotic Graft Injury by Dysregulating Mitochondrial Homeostasis in Living Donor Liver Transplantation. Ann Surg. 2022;276(5):e483–e492
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4380028892