PMID- 32860664 OWN - NLM STAT- MEDLINE DCOM- 20211213 LR - 20221005 IS - 2211-5463 (Electronic) IS - 2211-5463 (Linking) VI - 11 IP - 1 DP - 2021 Jan TI - PGC-1alpha is downregulated in a mouse model of obstructive cholestasis but not in a model of liver fibrosis. PG - 61-74 LID - 10.1002/2211-5463.12961 [doi] AB - Several studies have indicated that cholestatic liver damage involves mitochondria dysfunction. However, the precise mechanism by which hydrophobic bile salts cause mitochondrial dysfunction is not clear. In this study, we intended to determine the pathogenesis of cholestatic liver injury associated with peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha). A mouse model of cholestatic liver disease was generated by surgical ligation of the bile duct (BDL), and a mouse model of fibrosis was developed through serial administration of thioacetamide. After obtaining liver specimens on scheduled days, we compared the expression of the antioxidant enzymes (superoxide dismutase 2 [SOD2], catalase, and glutathione peroxidase-1[GPx-1]) and PGC-1alpha in livers from mice with fibrosis and cholestasis using western blotting, immunohistochemistry, and immunofluorescence. We found that cholestatic livers exhibit lower expression of antioxidant enzymes, such as SOD2, catalase, and PGC-1alpha. In contrast, fibrotic livers exhibit higher expression of antioxidant enzymes and PGC-1alpha. In addition, cholestatic livers exhibited significantly lower expression of pro-apoptotic markers (Bax) as compared to fibrotic livers. It is well known that overexpression of PGC-1alpha increases mitochondrial antioxidant enzyme expression, and vice versa. Thus, we concluded that obstructive cholestasis decreases expression of PGC-1alpha, which may lead to decreased expression of mitochondrial antioxidant enzymes, thereby rendering mice with cholestatic livers vulnerable to ROS-induced cell death. CI - (c) 2020 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. FAU - Park, Jung Hyun AU - Park JH AUID- ORCID: 0000-0003-2693-0655 AD - Department of Surgery, College of Medicine, Eunpyeong St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. FAU - Kwak, Bong Jun AU - Kwak BJ AUID- ORCID: 0000-0003-2409-9386 AD - Department of Surgery, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea. FAU - Choi, Ho Joong AU - Choi HJ AUID- ORCID: 0000-0002-0862-098X AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. FAU - Kim, Ok-Hee AU - Kim OH AUID- ORCID: 0000-0002-9204-2587 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. AD - Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea. FAU - Hong, Ha-Eun AU - Hong HE AUID- ORCID: 0000-0002-4361-4809 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. AD - Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea. FAU - Lee, Sang Chul AU - Lee SC AUID- ORCID: 0000-0002-8681-7059 AD - Department of Surgery, College of Medicine, Daejeon St. Mary's Hospital, the Catholic University of Korea, Daejeon, Korea. FAU - Kim, Kee-Hwan AU - Kim KH AD - Department of Surgery, College of Medicine, Uijeongbu St. Mary's Hospital, the Catholic University of Korea, Gyeonggi-do, Korea. FAU - You, Young Kyoung AU - You YK AUID- ORCID: 0000-0002-8506-0752 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. FAU - Lee, Tae Yun AU - Lee TY AUID- ORCID: 0000-0002-4414-7958 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. FAU - Ahn, Joseph AU - Ahn J AUID- ORCID: 0000-0001-8528-4919 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. FAU - Kim, Say-June AU - Kim SJ AUID- ORCID: 0000-0001-5171-4837 AD - Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea. AD - Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea. LA - eng PT - Journal Article DEP - 20201209 PL - England TA - FEBS Open Bio JT - FEBS open bio JID - 101580716 RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Reactive Oxygen Species) RN - 075T165X8M (Thioacetamide) RN - EC 1.11.1.6 (Catalase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.15.1.1 (superoxide dismutase 2) SB - IM MH - Animals MH - Bile Ducts/surgery MH - Catalase/metabolism MH - Cholestasis/etiology/*pathology MH - Disease Models, Animal MH - Down-Regulation MH - Humans MH - Ligation MH - Liver/cytology/enzymology/*pathology MH - Liver Cirrhosis, Experimental/chemically induced/*pathology MH - Male MH - Mice MH - Mitochondria/enzymology/pathology MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism MH - Reactive Oxygen Species/metabolism MH - Superoxide Dismutase/metabolism MH - Thioacetamide/administration & dosage/toxicity PMC - PMC7780111 OTO - NOTNLM OT - antioxidant enzymes OT - cholestatic liver disease OT - liver fibrosis OT - mitochondria OT - peroxisome proliferator-activated receptor-gamma co-activator 1alpha COIS- The authors declare no conflict of interest. EDAT- 2020/08/30 06:00 MHDA- 2021/12/15 06:00 PMCR- 2020/12/09 CRDT- 2020/08/30 06:00 PHST- 2020/02/09 00:00 [received] PHST- 2020/08/03 00:00 [revised] PHST- 2020/08/21 00:00 [accepted] PHST- 2020/08/30 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2020/08/30 06:00 [entrez] PHST- 2020/12/09 00:00 [pmc-release] AID - FEB412961 [pii] AID - 10.1002/2211-5463.12961 [doi] PST - ppublish SO - FEBS Open Bio. 2021 Jan;11(1):61-74. doi: 10.1002/2211-5463.12961. Epub 2020 Dec 9.