scholarly journals Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

Diabetes ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 76-90
Author(s):  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
Dominique Farabos ◽  
...  
Keyword(s):  
Lipid Storage ◽  
Cholesterol Homeostasis ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

scholarly journals Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2619
Author(s):  
Vinay Sachdev ◽  
Madalina Duta-Mare ◽  
Melanie Korbelius ◽  
Nemanja Vujić ◽  
Christina Leopold ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Metabolic Reprogramming ◽  
Whole Body ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7α-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis.

scholarly journals Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy

2020 ◽  
Author(s):  
Ada Admin ◽  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Blood Cholesterol ◽  
Autophagic Flux ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Expression Of Genes ◽  
Metabolic Role ◽  
Hypothermic Stress ◽  
Tissue Cholesterol

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.

scholarly journals Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy

2020 ◽  
Author(s):  
Ada Admin ◽  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Blood Cholesterol ◽  
Autophagic Flux ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Expression Of Genes ◽  
Metabolic Role ◽  
Hypothermic Stress ◽  
Tissue Cholesterol

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.

Lysosomal Acid Lipase Deficiency: Correction of Lipid Storage by Adenovirus-Mediated Gene Transfer in Mice

2002 ◽  
Vol 13 (11) ◽  
pp. 1361-1372 ◽  
Author(s):  
Hong Du ◽  
Martin Heur ◽  
David P. Witte ◽  
Detlev Ameis ◽  
Gregory A. Grabowski
Keyword(s):  
Gene Transfer ◽  
Lipid Storage ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Lysosomal Acid Lipase Deficiency

Phenotypic Correction of Lipid Storage and Growth Arrest in Wolman Disease Fibroblasts by Gene Transfer of Lysosomal Acid Lipase

2001 ◽  
Vol 12 (3) ◽  
pp. 279-289 ◽  
Author(s):  
Uwe J.F. Tietge ◽  
Gwoshing Sun ◽  
Susan Czarnecki ◽  
Qian-Chun Yu ◽  
Peter Lohse ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Growth Arrest ◽  
Lipid Storage ◽  
Acid Lipase ◽  
Wolman Disease ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase
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