title: Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids.
abstract: OBJECTIVE
  Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism.
  
  
  RESULTS
  We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects.
  
  
  CONCLUSIONS
  These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism.
authors: Public Health Genomics Unit, National Institute for Health and Welfare, Biomedicum, Helsinki, Finland.
authors: Marius R
authors: MR
authors: Robciuc
authors: Marianna
authors: M
authors: Maranghi
authors: Anna
authors: A
authors: Lahikainen
authors: Daniel
authors: D
authors: Rader
authors: Andre
authors: A
authors: Bensadoun
authors: Katariina
authors: K
authors: Öörni
authors: Katariina
authors: K
authors: Oörni
authors: Jari
authors: J
authors: Metso
authors: Ilenia
authors: I
authors: Minicocci
authors: Ester
authors: E
authors: Ciociola
authors: Fabrizio
authors: F
authors: Ceci
authors: Anna
authors: A
authors: Montali
authors: Marcello
authors: M
authors: Arca
authors: Christian
authors: C
authors: Ehnholm
authors: Matti
authors: M
authors: Jauhiainen
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000172:deficiency* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D015536:Down-Regulation; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007558:Italy; D016014:Linear Models; D008049:Lipase / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015415:Biomarkers; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; C504173:LIPC protein, human; D008077:Lipoproteins, LDL; D014280:Triglycerides; C410382:LIPG protein, human; D008049:Lipase; C548261:LPL protein, human; D008071:Lipoprotein Lipase
keywords: ANGPTL3 protein, human; ANGPTL4 protein, human; endothelial lipase, human; familial combined hypolipidemia; fatty acids, nonesterified; hepatic lipase, human; lipoprotein lipase