Trends in Endocrinology & Metabolism
ReviewRegulation of lipoprotein lipase by Angptl4
Section snippets
Regulation of plasma TG clearance
FA are a principal fuel for numerous cell types and serve as substrate for energy storage in fat tissue. A major portion of FA taken up by cells is transported through the blood as TG within chylomicrons and VLDL (see Glossary). Chylomicrons are formed from dietary TG and cholesterol in enterocytes and reach the bloodstream after passing through the splanchnic lymphatic system. VLDL are assembled from TG synthesized in liver and are secreted directly into the blood. In the circulation,
Structure of Angptl4
Similarly to other family members, Angptl4 can be divided into distinct regions: an N-terminal signal peptide, a region containing two separate coiled-coil domains, a linker region, and a large C-terminal fibrinogen-like domain 19, 20. During evolution, the C-terminal and N-terminal regions were present separately in different organisms, suggesting that the different domains of Angptl4 may have distinct physiological functions [20]. In agreement with that notion, full-length Angptl4 (flAngptl4,
Role of Angptl4 in physiological regulation of lipid metabolism
LPL and Angptl4 are regulated by changes in nutritional state in a tissue-specific manner, reflecting the different functions of these tissues and the corresponding variations in physiological requirements for lipids 13, 14, 46. Below, we discuss current knowledge on the regulation of Angptl4 and LPL in response to various physiological stimuli and address the importance of Angptl4 in lipid uptake. An overview of the role of Angptl4 in physiological regulation of lipid metabolism is presented
Clinical perspectives of Angptl4
In support of the mouse studies, genetic studies have provided support for a similar function of Angptl4 in humans. Specifically, a genetic loss-of-function variant of ANGPTL4 (E40K) that is found in 3% of European Americans is associated with reduced plasma TG levels [86]. Remarkably, none of the genome-wide association studies performed so far have linked single-nucleotide polymorphisms (SNPs) in or near the ANGPTL4 gene to plasma TG levels. Likewise, so far no positive correlation has been
Concluding remarks and future perspectives
In the past decade, angiopoietin-like proteins have been demonstrated to regulate plasma TG levels powerfully in mice and humans. The elucidation of these proteins as inhibitors of LPL activity has led to a paradigm shift in how clearance of circulating TG and thereby tissue uptake of FA are regulated. Most of our understanding of angiopoietin-like proteins has resulted from detailed study of Angptl4. It is becoming increasingly clear that a major portion of the physiological variation in LPL
Acknowledgments
We would like to thank Gunilla Olivecrona for fruitful discussion. This study was supported by grant 12CVD04 from the Fondation Leducq and by The Netherlands Organisation for Health Research and Development (NWO ZonMW).
Glossary
- Angiopoietin-like 4 (Angptl4)
- a ∼45–65 kDa glycosylated and secreted protein, a member of the angiopoietin-like gene family. Angptl4 contains a coiled-coil N-terminal domain and a fibrinogen-like C-terminal domain and is directly involved in the regulation of lipid metabolism via the inhibition of LPL activity. Angptl4 has also been linked to endothelial function, tumor biology, and wound healing.
- Chylomicrons
- large lipoproteins with high TG content that transport dietary lipids from the intestines
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