Zheyong Li1,2, Yuelong Liang1,2, Hanning Ying1,2, Mingyu Chen1,2, Xiaoyan He2,3, Yifan Wang1,2, Yifan Tong1,2, Xiujun Cai1,2. 1. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 2. Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 3. Department of Biological Treatment Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Abstract
BACKGROUND: The mechanism of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-induced rapid liver regeneration remains poorly documented, especially in patients with fibrosis. Therefore, this study aims to investigate the underlying mechanism of ALPPS-induced accelerated regeneration in toxin-induced fibrosis models. METHODS: The ALPPS-induced regeneration model was established in livers with thioacetamide (TAA)-induced fibrosis to determine the regenerative pathways involved in rapid regeneration. Confirmatory experiments were performed in transforming growth factor beta 1 (TGFβ1)-treated AML12 cells and mice with carbon tetrachloride (CCl4)-induced fibrosis. Finally, mitochondrial dysfunction was validated in fibrotic/non-fibrotic patients. RESULTS: In TAA-induced fibrotic mice, ALPPS-induced regeneration was significantly inferior to that of the control group (P=0.027 at day 2 and P<0.001 at day 7). Furthermore, mitochondria-associated genes were significantly downregulated in TAA-challenged mice. Accordingly, the reduced production of ATP and elevated levels of malondialdehyde indicated disturbances in intracellular energy metabolism during the ALPPS-induced regenerative process after TAA treatment. Further investigations were performed in TGF-β1-treated AML12 cells and CCl4-treated mice, which indicated that mitochondrial dysfunction attenuated the capacity for rapid regeneration after ALPPS. CONCLUSIONS: In summary, this study revealed that mitochondrial dysfunction led to inferior regeneration in livers with toxin-induced fibrosis and identified new therapeutic targets to improve the feasibility and safety of the ALPPS procedure. Further studies in human patients are required in the future. 2021 Annals of Translational Medicine. All rights reserved.
BACKGROUND: The mechanism of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-induced rapid liver regeneration remains poorly documented, especially in patients with fibrosis. Therefore, this study aims to investigate the underlying mechanism of ALPPS-induced accelerated regeneration in toxin-induced fibrosis models. METHODS: The ALPPS-induced regeneration model was established in livers with thioacetamide (TAA)-induced fibrosis to determine the regenerative pathways involved in rapid regeneration. Confirmatory experiments were performed in transforming growth factor beta 1 (TGFβ1)-treated AML12 cells and mice with carbon tetrachloride (CCl4)-induced fibrosis. Finally, mitochondrial dysfunction was validated in fibrotic/non-fibrotic patients. RESULTS: In TAA-induced fibrotic mice, ALPPS-induced regeneration was significantly inferior to that of the control group (P=0.027 at day 2 and P<0.001 at day 7). Furthermore, mitochondria-associated genes were significantly downregulated in TAA-challenged mice. Accordingly, the reduced production of ATP and elevated levels of malondialdehyde indicated disturbances in intracellular energy metabolism during the ALPPS-induced regenerative process after TAA treatment. Further investigations were performed in TGF-β1-treated AML12 cells and CCl4-treated mice, which indicated that mitochondrial dysfunction attenuated the capacity for rapid regeneration after ALPPS. CONCLUSIONS: In summary, this study revealed that mitochondrial dysfunction led to inferior regeneration in livers with toxin-induced fibrosis and identified new therapeutic targets to improve the feasibility and safety of the ALPPS procedure. Further studies in human patients are required in the future. 2021 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS); fibrosis; mitochondrial dysfunction; regeneration
Authors: A Budai; G Horváth; L Tretter; Z Radák; E Koltai; Z Bori; F Torma; Á Lukáts; P Röhlich; A Szijártó; A Fülöp Journal: Br J Surg Date: 2018-09-27 Impact factor: 6.939
Authors: Tatiana Kisseleva; Min Cong; Yonghan Paik; David Scholten; Chunyan Jiang; Chris Benner; Keiko Iwaisako; Thomas Moore-Morris; Brian Scott; Hidekazu Tsukamoto; Sylvia M Evans; Wolfgang Dillmann; Christopher K Glass; David A Brenner Journal: Proc Natl Acad Sci U S A Date: 2012-05-07 Impact factor: 11.205