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.