Role Of Angiopoietin-Like 3 And 4 in Triacylglycerol Metabolism : From population studies to molecular mechanisms of action

83 Excessive accumulation of triacylglycerols in circulation (hypertriglyceridemia) and/or in adipose tissue (obesity) are major risk factors for type 2 diabetes and cardiovascular diseases, two major morbidities worldwide. This thesis provides insights into the function of angiopoietin-like 3 and 4 in human triacylglycerol metabolism. Immunological assays have been developed and used to show that circulating levels of angiopoietin-like 3 and 4 have no or minor effects on plasma triacylglycerol levels. In the case of Angptl3 only complete absence of the protein in plasma, due to a nonsense mutation, generated dramatic changes not only in triacylglycerols but also in all major plasma lipoproteins and lipids, a phenotype referred to as familial combined hypolipidemia. Further studies presented in this book support a more subtle role for angiopoietin-like 4 at tissue level in regulating the key enzyme in plasma triacylglycerol metabolism, lipoprotein lipase. Study of monozygotic twins and human adipocytes in culture revealed a role for angiopoietin-like 4 in regulating fat content of adipose tissue.