RT Journal Article
SR Electronic
T1 Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy.
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP db200578
DO 10.2337/db20-0578
A1 Gamblin, Camille
A1 Rouault, Christine
A1 Lacombe, Amélie
A1 Langa-Vives, Francina
A1 Farabos, Dominique
A1 Lamaziere, Antonin
A1 Clément, Karine
A1 Gautier, Emmanuel L.
A1 Yvan-Charvet, Laurent
A1 Dugail, Isabelle
YR 2020
UL http://diabetes.diabetesjournals.org/content/early/2020/10/29/db20-0578.abstract
AB Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes is unclear. We show that the isolated adipocyte fraction but not the total undigested adipose tissue from obese patients has decreased LAL expression compared to non-obese. Lentiviral-mediated LAL knockdown in 3T3L1 to mimic obese adipocytes condition did not affect lysosome density or autophagic flux, but increased triglyceride storage and disrupted ER cholesterol as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than controls on a high fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol was lower than controls albeit similar triglyceridemia. Adipose-LAL overexpressing mice phenotype is dependent on the housing temperature, and develops only under mild hypothermic stress (room temperature) but not at thermoneutrality (30°C), demonstrating prominent contribution of BAT thermogenesis. LAL overexpression increased BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue cholesterol homeostasis and impacts BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.