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

Abstract

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 lysosomederived 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.

Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet

“…We also show that overexpression drives inflammation and promotes a large influx of immune cells into the liver. This is contrary to overexpression of LIPA in adipose tissue which showed reduced inflammation and no changes in autophagy 20 suggesting that the liver may be particularly sensitive to alterations of lysosomal lipid degradation and signaling.…”

“…Recent work also identifies lipophagy inhibition in clinical samples of NAFLD patients 18 , leading some to suggest testing LAL replacement therapy as a potential treatment for diet-induced liver disease 19 . A mouse model of LAL overexpression in adipose tissue prevented diet-induced weight gain and lowered J o u r n a l P r e -p r o o f circulating cholesterol 20 . However, the potential impacts of liver specific overexpression of LAL are unknown.…”

Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation

“…46,47 Adipocyte-specific Lipa overexpression also reduces blood cholesterol levels in HFD-fed mice and Lipa deficiency leads to impaired formation of HDL in LDL-loaded human dermal fibroblasts. 48,49 Decreased Lipa expression in SMCs could also decrease free cholesterol uptake in the Perk SMC−/− SMCs but did not prevent formation of SMC foam cells in the Perk SMC−/− aortic walls.…”

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

“…LAL-derived fatty acids (FA) are a critical source of precursors for the synthesis of lipid mediators [13]. We and others have shown that LAL is critical for the maintenance of FA metabolism and overall energy homeostasis [14,15]. In the livers of LAL-KO mice, reduced FA availability leads to impaired very-low-density lipoprotein (VLDL) secretion with concomitant improved insulin sensitivity and glucose tolerance [16].…”