title: Sirt1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet.
abstract: OBJECTIVE
  Heme oxygenase 1 (HO-1)-mediated increases in adiponectin, ameliorate the deleterious effects of obesity and metabolic syndrome; however, the effect of HO-1 on hepatic lipid metabolism remains elusive. The aim of this study is to evaluate the role of HO-1 in hepatic lipid metabolism.
  
  
  METHODS
  Functional studies were performed using C57BL/6J (WT) mice and Sirt1 liver specific mutant (Sirt1-deficient) mice. The molecular mechanism was explored in primary hepatocytes and mouse liver.
  
  
  RESULTS
  Chronic exposure to high-fat diet (HFD) induced hepatic steatosis in WT mice. Treatment of WT mice on HFD with cobalt protoporphyrin (CoPP), an inducer of HO-1 activity, decreased body weight and visceral fat content, reduced intracellular hepatic triglyceride and serum total cholesterol concentrations, and decreased liver lipid droplet formation. Compared with WT mice, the administration of CoPP to Sirt1-deficient mice on HFD increased visceral fat content, and slightly promoted liver lipid droplet formation. CoPP improved glucose tolerance and insulin sensitivity in WT mice on HFD, but compromised insulin sensitivity in Sirt1-deficient mice on HFD. Furthermore, CoPP-induced Sirt1 expression and decreased sterol regulatory element binding protein 1c (SREBP-1c) expression in WT mice on HFD. However, CoPP promoted SREBP-1c expression in Sirt1-deficient hepatocytes, which was reversed by a protein tyrosine phosphatase 1b inhibitor. Additionally, while the administration of CoPP to WT mice on HFD improved antioxidant and anti-inflammatory states, these CoPP-mediated effects were abolished in Sirt1-deficient mice.
  
  
  CONCLUSIONS
  Sirt1 mediates the effect of CoPP on ameliorating liver metabolic damage caused by HFD.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: xiaojunliu@ibms.pumc.edu.cn.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Meixia
authors.initials: M
authors.lastname: Li
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Geng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Xu
authors.affiliation: The Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
authors.forename: Yaoguo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiao
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: fangfd@vip.sina.com.
authors.forename: Fude
authors.initials: F
authors.lastname: Fang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: changy@ibms.pumc.edu.cn.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000502:physiology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology; D011524:Protoporphyrins / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology
chemical_list: D011524:Protoporphyrins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: HO-1; Inflammation; Metabolism; Mitochondrial biogenesis; SREBP-1c; Sirt1