Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase

Biochim Biophys Acta. 2016 Feb;1861(2):130-137. doi: 10.1016/j.bbalip.2015.11.003. Epub 2015 Nov 11.

Abstract

Aim: 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).

Conclusion: 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.

Keywords: ANGPTL8; ATGL; Betatrophin; Histidine deprivation; Stress protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Angiopoietin-Like Protein 8
  • Angiopoietin-like Proteins
  • Angiopoietins / genetics*
  • Angiopoietins / metabolism
  • Angiopoietins / pharmacology
  • Animals
  • Cell Differentiation
  • Cell Line
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Culture Media / chemistry
  • Culture Media / pharmacology
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Gene Expression Regulation
  • Glycerol / metabolism
  • Hep G2 Cells
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Lipase / genetics*
  • Lipase / metabolism
  • Lipid Metabolism / drug effects
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Triglycerides / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • ANGPTL8 protein, mouse
  • Angiopoietin-Like Protein 8
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Atf4 protein, mouse
  • CCN2 protein, mouse
  • Culture Media
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Recombinant Proteins
  • Triglycerides
  • Connective Tissue Growth Factor
  • Activating Transcription Factor 4
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • Lipase
  • PNPLA2 protein, mouse
  • ras Proteins
  • Glycerol