Regulation of triglyceride metabolism by angiopoietin-like proteins

F.B.J. Mattijssen, A.H. Kersten

Research output: Contribution to journalReview articleAcademicpeer-review

96 Citations (Scopus)

Abstract

asma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
Original languageEnglish
Pages (from-to)782-789
Number of pages8
JournalBiochimica et Biophysica Acta. Molecular and Cell Biology of Lipids
Volume1821
Issue number5
DOIs
Publication statusPublished - 2012

Fingerprint

Angiopoietins
Lipoprotein Lipase
Triglycerides
Peroxisome Proliferator-Activated Receptors
Proteins
Fasting
Fatty Acids
Chylomicrons
Genome-Wide Association Study
Liver
Medical Genetics
Nonesterified Fatty Acids
Knockout Mice
Transgenic Mice
Lipoproteins
Intestines
Gene Expression

Keywords

  • activated receptor-beta/delta
  • lipoprotein-lipase activity
  • diet-induced obesity
  • coiled-coil domain
  • proprotein convertases
  • ppar-beta/delta
  • adipose-tissue
  • growth-factor
  • fatty-acids
  • plasma triglyceride

Cite this

@article{f735d5ff78d0421aa45c207bfe5c9ac4,
title = "Regulation of triglyceride metabolism by angiopoietin-like proteins",
abstract = "asma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.",
keywords = "activated receptor-beta/delta, lipoprotein-lipase activity, diet-induced obesity, coiled-coil domain, proprotein convertases, ppar-beta/delta, adipose-tissue, growth-factor, fatty-acids, plasma triglyceride",
author = "F.B.J. Mattijssen and A.H. Kersten",
year = "2012",
doi = "10.1016/j.bbalip.2011.10.010",
language = "English",
volume = "1821",
pages = "782--789",
journal = "Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids",
issn = "1388-1981",
publisher = "Elsevier",
number = "5",

}

Regulation of triglyceride metabolism by angiopoietin-like proteins. / Mattijssen, F.B.J.; Kersten, A.H.

In: Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids, Vol. 1821, No. 5, 2012, p. 782-789.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Regulation of triglyceride metabolism by angiopoietin-like proteins

AU - Mattijssen, F.B.J.

AU - Kersten, A.H.

PY - 2012

Y1 - 2012

N2 - asma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

AB - asma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

KW - activated receptor-beta/delta

KW - lipoprotein-lipase activity

KW - diet-induced obesity

KW - coiled-coil domain

KW - proprotein convertases

KW - ppar-beta/delta

KW - adipose-tissue

KW - growth-factor

KW - fatty-acids

KW - plasma triglyceride

U2 - 10.1016/j.bbalip.2011.10.010

DO - 10.1016/j.bbalip.2011.10.010

M3 - Review article

VL - 1821

SP - 782

EP - 789

JO - Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids

JF - Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids

SN - 1388-1981

IS - 5

ER -