RESUMO
Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions. Furthermore, pharmacological inhibition or genetic ablation of LAL in murine liver largely reduced in vitro acid RE hydrolase activity. Interestingly, LAL-deficient mice exhibited increased RE content in the duodenum and jejunum but decreased RE content in the liver. Furthermore, LAL-deficient mice challenged with RE gavage exhibited largely reduced post-prandial circulating RE content, indicating that LAL is required for efficient nutritional vitamin A availability. In summary, our results indicate that LAL is the major acid RE hydrolase and required for functional retinoid homeostasis.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Duodeno/enzimologia , Jejuno/enzimologia , Retinoides/metabolismo , Esterol Esterase/metabolismo , Animais , Hidrolases de Éster Carboxílico/genética , Ésteres do Colesterol/genética , Ésteres do Colesterol/metabolismo , Remanescentes de Quilomícrons/genética , Remanescentes de Quilomícrons/metabolismo , Humanos , Camundongos , Camundongos Knockout , Retinoides/genética , Esterol Esterase/genética , Triglicerídeos/genética , Triglicerídeos/metabolismoRESUMO
The recent discovery of a dysfunctional mutation of GPIHBP1 in a man with chylomicronemia implicates this protein in human physiology. GPIHBP1 can be placed in the larger context of other molecular participants in chylomicron docking and hydrolysis on microvascular endothelium, caloric delivery, and remnant lipoprotein generation. Critical questions include the regulation--and dysregulation--of these processes in states of overnutrition, underexertion, obesity, insulin resistance, and diabetes.