Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2420-2427
Published online before print August 30, 2007, doi: 10.1161/ATVBAHA.107.151894
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
27/11/2420    most recent
ATVBAHA.107.151894v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lichtenstein, L.
Right arrow Articles by Kersten, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lichtenstein, L.
Right arrow Articles by Kersten, S.
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2420.)
© 2007 American Heart Association, Inc.


Atherosclerosis and Lipoproteins

Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake

Laeticia Lichtenstein; Jimmy F.P. Berbée; Susan J. van Dijk; Ko Willems van Dijk; André Bensadoun; Ido P. Kema; Peter J. Voshol; Michael Müller; Patrick C.N. Rensen; Sander Kersten

From the Nutrigenomics Consortium (L.L., K.W.v.D., M.M., S.K.), TI Food and Nutrition, Wageningen, the Netherlands; Nutrition, Metabolism, and Genomics group (L.L., S.J.v.D., M.M., S.K.), Wageningen University, Wageningen, the Netherlands; the Departments of General Internal Medicine (J.F.P.B., K.W.v.D., P.C.N.R.), Endocrinology and Metabolic Diseases (J.F.P.B., P.J.V., P.C.N.R.), and Human Genetics (K.W.v.D.), Leiden University Medical Center, Leiden, the Netherlands; the Division of Nutritional Sciences (A.B.), Cornell University, Ithaca, NY; and Pathology and Laboratory Medicine (I.P.K.), University Medical Center Groningen, Groningen, the Netherlands.

Correspondence to Sander Kersten, PhD, Nutrition, Metabolism, and Genomics group, Wageningen University, PO BOX 8129, 6700EV Wageningen The Netherlands. E-mail sander.kersten{at}wur.nl

Background— Dysregulation of plasma lipoprotein levels may increase the risk for atherosclerosis. Recently, angiopoietin-like protein 4, also known as fasting-induced adipose factor Fiaf, was uncovered as a novel modulator of plasma lipoprotein metabolism. Here we take advantage of the fasting-dependent phenotype of Angptl4-transgenic (Angptl4-Tg) mice to better characterize the metabolic function of Angptl4.

Methods and Results— In 24-hour fasted mice, Angptl4 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/LDL- and HDL-TG content. Angptl4 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angptl4 overexpression severely impaired LPL-dependent plasma TG and cholesteryl ester clearance and subsequent uptake of fatty acids and cholesterol into tissues. Consequently, hepatic cholesterol content was significantly decreased, leading to universal upregulation of cholesterol and fatty acid synthesis pathways and increased rate of cholesterol synthesis.

Conclusions— The hypertriglyceridemic effect of Angptl4 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angptl4 upregulates cholesterol synthesis in liver secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.

The present study exploits the fasting-dependent phenotype of Angptl4-transgenic mice to characterize the function of Angptl4. We conclude that: (1) Angptl4 causes hypertriglyceridemia by inhibiting LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and (2) Angptl4 upregulates hepatic cholesterol synthesis secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.


Key Words: Angptl4 • lipoprotein lipase • cholesterol • triglycerides • liver




This article has been cited by other articles:


Home page
J. Lipid Res.Home page
D. B. van Schalkwijk, A. A. de Graaf, B. van Ommen, K. van Bochove, P. C. N. Rensen, L. M. Havekes, N. C. A. van de Pas, H. C. J. Hoefsloot, J. van der Greef, and A. P. Freidig
Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size
J. Lipid Res., December 1, 2009; 50(12): 2398 - 2411.
[Abstract] [Full Text] [PDF]


Home page
J. Lipid Res.Home page
S. Kersten and A. Bensadoun
Stabilizing lipoprotein lipase
J. Lipid Res., December 1, 2009; 50(12): 2335 - 2336.
[Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
L. M. Sanderson, T. Degenhardt, A. Koppen, E. Kalkhoven, B. Desvergne, M. Muller, and S. Kersten
Peroxisome Proliferator-Activated Receptor {beta}/{delta} (PPAR{beta}/{delta}) but Not PPAR{alpha} Serves as a Plasma Free Fatty Acid Sensor in Liver
Mol. Cell. Biol., December 1, 2009; 29(23): 6257 - 6267.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Endocrinol. Metab.Home page
H. Wang and R. H. Eckel
Lipoprotein lipase: from gene to obesity
Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E271 - E288.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
D. C. Berry and N. Noy
All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor {beta}/{delta} and Retinoic Acid Receptor
Mol. Cell. Biol., June 15, 2009; 29(12): 3286 - 3296.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
S. Kersten, L. Lichtenstein, E. Steenbergen, K. Mudde, H. F.J. Hendriks, M. K. Hesselink, P. Schrauwen, and M. Muller
Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids
Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 969 - 974.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
W. Yin, S. Romeo, S. Chang, N. V. Grishin, H. H. Hobbs, and J. C. Cohen
Genetic Variation in ANGPTL4 Provides Insights into Protein Processing and Function
J. Biol. Chem., May 8, 2009; 284(19): 13213 - 13222.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
M.-h. Yau, Y. Wang, K. S. L. Lam, J. Zhang, D. Wu, and A. Xu
A Highly Conserved Motif within the NH2-terminal Coiled-coil Domain of Angiopoietin-like Protein 4 Confers Its Inhibitory Effects on Lipoprotein Lipase by Disrupting the Enzyme Dimerization
J. Biol. Chem., May 1, 2009; 284(18): 11942 - 11952.
[Abstract] [Full Text] [PDF]


Home page
DiabetesHome page
P. Narvekar, M. Berriel Diaz, A. Krones-Herzig, U. Hardeland, D. Strzoda, S. Stohr, M. Frohme, and S. Herzig
Liver-Specific Loss of Lipolysis-Stimulated Lipoprotein Receptor Triggers Systemic Hyperlipidemia in Mice
Diabetes, May 1, 2009; 58(5): 1040 - 1049.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
L. Shan, X.-C. Yu, Z. Liu, Y. Hu, L. T. Sturgis, M. L. Miranda, and Q. Liu
The Angiopoietin-like Proteins ANGPTL3 and ANGPTL4 Inhibit Lipoprotein Lipase Activity through Distinct Mechanisms
J. Biol. Chem., January 16, 2009; 284(3): 1419 - 1424.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
P. J. Talmud, M. Smart, E. Presswood, J. A. Cooper, V. Nicaud, F. Drenos, J. Palmen, M. G. Marmot, S. M. Boekholdt, N. J. Wareham, et al.
ANGPTL4 E40K and T266M: Effects on Plasma Triglyceride and HDL Levels, Postprandial Responses, and CHD Risk
Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2319 - 2325.
[Abstract] [Full Text] [PDF]