MOLECULAR PATHOBIOLOGY OF THE HUMAN LIPOPROTEIN-LIPASE GENE

Lipoprotein lipase (LPL; E.C. 3.1.1.34) is a key enzyme in the metabol ism of lipids, Many diseases, including obesity, coronary heart diseas e, chylomicronemia (pancreatitis), and atherosclerosis, appear to be d irectly or indirectly related to abnormalities in LPL function, Human LPL is a member of a superfamily of lipases that includes hepatic lipa se and pancreatic lipase, These lipases are characterized by extensive homology, both at the level of the gene and the mature protein, sugge sting that they have a common evolutionary origin, A large number of n atural mutations have been discovered in the human LPL gene, which are located at different sites in the gene and affect different functions of the mature protein, There is a high prevalence of two of these mut ations (207 and 188) in the Province of Quebec, and one of them (207) is almost exclusive to the French Canadian population, A study of thes e and other naturally occurring mutant LPL molecules, as well as those created in vitro by site directed mutagenesis, indicate that the sequ ence of LPL is organized into multiple structural and functional units that act in concert in the normal enzyme, In this review, we discuss the interrelationships of LPL structure and its function, the molecula r etiology of abnormal LPL in humans, and the clinical and therapeutic aspects of LPL deficiency.