Genetics and regulation of angiopoietin-like proteins 3 and 4

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Abstract
Lipoprotein lipase activity in a given tissue is the rate limiting step for the uptake of triglyceride-derived fatty acids. Imbalances in the partitioning of fatty acids have major metabolic consequences. Given the central role of lipoprotein lipase in energy metabolism, the discovery of new molecules that affect the activity of lipoprotein lipase holds great potential for novel therapeutic targets. Angiopoietin-like proteins 3 and 4 are two members of the angiopoietin-like family of proteins (Angptl). Unique within this family, Angptl3 and 4 inhibit lipoprotein metabolism via their ability to inhibit the activity of lipoprotein lipase. This review highlights recent studies on the biochemistry of Angptl3 and 4 as well as mouse models with selective overexpression of Angptl4 or global knockout of Angptl3, 4, or both. Both angiopoietins and angiopoietin-like proteins share similar domain structures. Angptl3 and 4 are the only two members of this superfamily that inhibit lipoprotein lipase activity. However, Angptl3 and 4 are differentially regulated at multiple levels, suggesting non-redundant functions in vivo. Angptl3 and 4 are proteolytically processed into two halves and are differentially regulated by nuclear receptors. Transgenic overexpression of Angptl4 as well as knockout of Angptl3 or 4 demonstrate that these two proteins play essential roles in lipoprotein metabolism: liver-derived Angptl3 inhibits lipoprotein lipase activity primarily in the fed state, while Angptl4 plays important roles in both fed and fasted states. In addition, Angptl4 regulates the tissue-specific delivery of lipoprotein-derived fatty acids. Angptl4 is thus an endocrine or autocrine/paracarine inhibitor of lipoprotein lipase depending on its sites of expression.
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