title: Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase.
abstract: OBJECTIVE
  Atypical angiopoietin-like 8 (ANGPTL8), also known as betatrophin, is known to regulate lipid metabolism. However, its mechanism of action remains elusive.
  
  
  METHODS
  HepG2, 3T3-L1, and NIT-1 cells were cultured in amino acid-complete MEM or histidine-free MEM to detect ANGPTL8 expression. The three cell types were treated with or without recombinant ANGPTL8 to investigate its role in lipid metabolism. Hydrodynamic tail vein gene delivery was also used to examine the role of ANGPTL8 in mice.
  
  
  RESULTS
  ANGPTL8 is significantly up-regulated in amino acid-deprived cultured cells in vitro. The activation of ANGPTL8 gene transcription was mediated through the RAS/c-RAF/MAPK signaling pathway rather than the general GCN2/ATF4 pathways. ANGPTL8 activated the ERK signal transduction pathway in hepatocytes, adipocytes, and pancreatic β-cells, up-regulating early growth response transcription factor (Egr1) and down-regulating adipose triglyceride lipase (ATGL).
  
  
  CONCLUSIONS
  ANGPTL8 is a stress-response protein that regulates fat metabolism by suppressing ATGL expression, revealing a mechanistic connection between ANGPTL8 and lipid homeostasis in mammalian cells.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA; Center for Stem Cell and Regenerative Medicine, The Second Hospital of Shandong University, Jinan 250012, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Shiwu
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: William
authors.initials: W
authors.lastname: Donelan
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Stem Cell and Regenerative Medicine, The Second Hospital of Shandong University, Jinan 250012, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Purich
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
authors.affiliation: Center for Stem Cell and Regenerative Medicine, The Second Hospital of Shandong University, Jinan 250012, PR China. Electronic address: tangdq@sdu.edu.cn.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: yanglj@pathology.ufl.edu.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
mesh_terms: D041721:3T3-L1 Cells; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005990:Glycerol / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D051701:Activating Transcription Factor 4; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D055513:Connective Tissue Growth Factor; D003470:Culture Media; D051766:Early Growth Response Protein 1; D005990:Glycerol; D008049:Lipase; D020928:Mitogen-Activated Protein Kinases; D019908:Proto-Oncogene Proteins c-raf; D011994:Recombinant Proteins; D014280:Triglycerides; D018631:ras Proteins; C000595899:ANGPTL8 protein, mouse; C081452:Atf4 protein, mouse; C526318:CCN2 protein, mouse; C486109:Egr1 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: ANGPTL8; ATGL; Betatrophin; Histidine deprivation; Stress protein