医学
脂肪变性
安普克
线粒体生物发生
肝移植
再灌注损伤
肝损伤
内科学
线粒体
脂肪肝
缺血
移植
细胞生物学
生物
蛋白激酶A
疾病
磷酸化
作者
Liu Jiang,Li Pang,Kevin Tak‐Pan Ng,Ting‐Lan Chiu,Hui Liu,Xiaobing Liu,Aimin Xu,C. P. Lo,Kwan Man
出处
期刊:Annals of Surgery
[Ovid Technologies (Wolters Kluwer)]
日期:2020-09-01
卷期号:276 (5): e483-e492
被引量:9
标识
DOI:10.1097/sla.0000000000004468
摘要
Objective: To investigate the association of graft steatosis with long-term outcome, and to elucidate the mechanism of steatotic graft injury in adult living donor liver transplantation. Summary of Background Data: The utilization of steatotic graft expands the donor pool for living donor liver transplantation (LDLT). However, it remains controversial due to its high morbidity and mortality. Elucidating the mechanism of steatotic graft injury is crucial to develop therapeutic strategies targeting at graft injury and to further expand the donor pool. Methods: Five hundred thirty patients receiving LDLT were prospectively included for risk factor analysis and outcome comparison. Rat orthotopic liver transplantation, in vitro functional experiments and mouse hepatic ischemia/ reperfusion models were established to explore the mechanisms of steatotic graft injury. Results: We identified that graft with >10% steatosis was an independent risk factor for long-term graft loss after LDLT (hazard ratio 2.652, P = 0.001), and was associated with shorter cancer recurrence-free survival and acute phase liver injury. Steatotic graft displayed distinct mitochondrial dysfunction, including membrane, calcium, and energy homeostasis dysregulation. Specifically, the mitochondrial biogenesis was remarkably downregulated in steatotic graft. Inhibition of AMPK-PGC1α axis impaired mitochondrial biogenesis and was lethal to fatty hepatocyte in vitro , whereas reactivation of AMPK promoted PGC1α-mediated mitochondrial biogenesis and attenuated liver injury via restoring mitochondrial function in animal model. Conclusions: We provided a new mechanism that compromised AMPK-PGC1α axis exacerbated steatotic graft injury in LDLT by dysregulating mitochondrial homeostasis through impairment of biogenesis.
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