Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism

Endocrinology. 2005 Nov;146(11):4943-50. doi: 10.1210/en.2005-0476. Epub 2005 Aug 4.

Abstract

Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angptl)3 and Angptl4 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4- and Angptl3-deficient mice as well as transgenic mice overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angptl proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.

MeSH terms

  • Angiopoietin-like 4 Protein
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Animals
  • Fasting / blood
  • Heparin / pharmacology
  • Humans
  • Hyperlipidemias / blood
  • Hyperlipidemias / etiology
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lipoprotein Lipase / antagonists & inhibitors
  • Lipoprotein Lipase / blood
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Postprandial Period
  • Recombinant Proteins / pharmacology
  • Survival Analysis
  • Triglycerides / blood*

Substances

  • ANGPTL3 protein, human
  • ANGPTL4 protein, human
  • Angiopoietin-like 4 Protein
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Intercellular Signaling Peptides and Proteins
  • Recombinant Proteins
  • Triglycerides
  • Heparin
  • Lipoprotein Lipase