Research Project
2377807
Lipoprotein lipase (LPL) is a hydrolytic enzyme which is synthesized in a restricted number of animal tissues (e.g., human adipose, skeletal muscle, heart, intestine), but functions at the luminal surface of the vascular endothelium. LPL plays a critical role in normal mammalian energy homeostasis by removing circulating plasma triglycerides which are contained in chylomicron and very low density lipoprotein (VLDL) particles, and providing free fatty acids to adipocytes for storage, and to muscle for combustion. Studies of the relationship between LPL enzyme activity and fatty acid uptake by adipocytes suggest that LPL plays an important role in the maintenance of stored triglycerides in this tissue. The importance of LPL activity in normal lipoprotein metabolism is further supported by the observations that human patients with either LPL, or apolipoprotein CII (a necessary co-factor of LPL hydrolytic activity) deficiency accumulate VLDL and chylomicron particles in their plasma and are severely hypertriglyceredemic. In cases of severe hypertriglyceridemia adipocyte LPL levels are reduced and often associated with a decreased ability of this tissue to accumulate triglycerides. Genetic forms of obesity and physiological perturbations, such as diet-induced obesity, however, result in elevated adipose LPL levels. LPL expression and enzyme activity represents one of the earliest measurable developmental events in developing precursor, or "pre- adipocyte" cells, and its activity increases dramatically during adipocyte maturation; hence, LPL is an important phenotypic marker of adipocyte differentiation. These tissue-specific changes in LPL activity in normal, and patho- physiological states suggest that fatty acid metabolism is differentially regulated to maintain body weight and to partition fuel, and moreover, that regulation of LPL activity in association with triglyceride metabolism involves control at many levels in the developing and mature adipocyte. Our goals are to study the metabolic signals which regulate LPL during adipocyte differentiation. Our approach is to use several mouse adipogenic cell lines which differentiate under defined hormonal and metabolic conditions in culture. Through dissection of metabolic signals and pathways which regulate LPL in a tissue-specific manner insight will be gained into mechanisms which control LPL expression, and the commitment of pre-adipocytes to adipogenesis. Our long-range goal is to establish a human adipogenic cell line from primary human tissue for purposes of studying human LPL regulation and signaling events which control adipocyte differentiation. Using these cell culture adipocyte model systems a better understanding of cellular metabolic events which serve to regulate the tissue-specific expression of LPL will be achieved.
