RESUMEN
Adipocyte triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are intracellular lipases that mobilize triglycerides, the main energy source in mammals. Deletion of genes encoding ATGL (Pnpla2) or HSL (Lipe) in mice results in striking phenotypic differences, suggesting distinct roles for these lipases. The goal of the present study was to identify the biological processes that are modulated in the metabolic tissues of ATGL- and HSL-deficient mice. DNA microarrays were employed to provide full genome coverage concerning the types of genes that are differentially expressed in wild-type and mutant mice. For both mouse models, transcript signatures were identified in white adipose tissue, brown adipose tissue (BAT), skeletal muscle (SM), cardiac muscle (CM), and liver. Genetic ablation of ATGL and HSL alters the transcript levels of a large number of genes in metabolic tissues. The genes affected in the two models are, however, largely different ones. Indeed, only one biological process was modulated in the same way in both mouse models, namely the down-regulation of fatty acid metabolism in BAT. The most pronounced modulation of biological processes was observed in ATGL-/- CM, in which a concerted down-regulation of transcripts associated with oxidative pathways was observed. In HSL-/- mice, in contrast, the most marked changes were seen in SM, namely, alterations in transcript levels reflecting a change of energy source from lipid to carbohydrate. The transcript signatures also provided novel insights into the metabolic derangements that are characteristic of ATGL-/- mice. Our findings suggest that ATGL and HSL differentially modulate biological processes in metabolic tissues. We hypothesize that the intermediary metabolites of the lipolytic pathways are signaling molecules and activators of a wide range of biochemical and cellular processes in mammals.
Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Regulación Enzimológica de la Expresión Génica , Metabolismo de los Lípidos/genética , Esterol Esterasa/genética , Animales , Regulación hacia Abajo , Metabolismo Energético/genética , Lipasa , Lipólisis/genética , Ratones , Ratones Mutantes , Termogénesis/genética , Distribución Tisular , Transcripción GenéticaRESUMEN
PURPOSE OF REVIEW: The aim of this review is to summarize and discuss recent advances in the understanding of the physiological role of lipoprotein lipase in lipid and energy metabolism. RECENT FINDINGS: Studies on the transcriptional and the posttranscriptional level of lipoprotein lipase expression have provided new insights into the complex mechanisms that are involved in the regulation of the enzyme. Additionally a large body of evidence from both human studies and animal models suggests that the level of lipoprotein lipase expression in a given tissue is the rate limiting process for the uptake of triglyceride derived fatty acids. Imbalances in the partitioning of fatty acids among peripheral tissues have major metabolic consequences. For example, in mice both decreased lipoprotein lipase activities in adipose tissue and increased activity in muscle are associated with resistance to obesity; lack of lipoprotein lipase activity in macrophages is correlated with a decreased susceptibility to develop atherosclerotic lesions and overexpression of the enzyme in muscle is associated with increased blood glucose levels and insulin resistance. SUMMARY: Considering the central role of lipoprotein lipase in energy metabolism it is a reasonable goal to discover and develop new drugs that affect the tissue specific expression pattern of the enzyme.