溶酶体酸性脂肪酶（LAL）是唯一能在酸性pH下分解胆固醇酯和三酰甘油的溶酶体酶。LAL活性受损导致LAL缺乏症（LAL-D），这是一种以异位溶酶体脂质积累为特征的严重和致命的疾病。降低的LAL活性也会促进非酒精性脂肪肝病（NAFLD）的发展和进展。为了推进我们对LAL相关肝脏病理学的理解，我们对全身遗传LAL丢失的小鼠（Lal-/-）和肝细胞特异性LAL-D的小鼠（hepLal-/-）的肝脏进行了全面的蛋白质组学分析。Lal-/-小鼠表现出明显的蛋白质组变化，包括与代谢、炎症、肝纤维化和癌症相关的多种蛋白质的失调。Lal-/-肝脏中LAL活性的全面丧失影响了酸性和中性脂肪酶活性，导致肝脏脂质积累，表明Lal-/-肝脏发生了完全的代谢转变。肝脏炎症和免疫细胞浸润是明显的，有大量上调的与炎症相关的基因本体生物过程术语。相比之下，年轻和成熟的hepLal-/-小鼠的肝脏蛋白质组仅显示出轻微的变化，表明仅在肝细胞中丧失LAL不会在小鼠中复制出观察到的代谢变化。这些发现为我们理解LAL-D中肝脏功能障碍的机制提供了有价值的见解，并可能有助于理解降低的LAL活性如何导致NAFLD。我们的研究凸显了LAL在维持肝脏稳态方面的重要性，并展示了其全身缺乏对肝脏蛋白质组和肝脏功能的重大影响。版权所有 © 2023作者。由Elsevier Inc.出版。保留所有权利。

Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal-/-) and from mice with hepatocyte-specific LAL-D (hepLal-/-). Lal-/- mice exhibited drastic proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer. Global loss of LAL activity impaired both acidic and neutral lipase activities and resulted in hepatic lipid accumulation, indicating a complete metabolic shift in Lal-/- livers. Hepatic inflammation and immune cell infiltration were evident, with numerous upregulated inflammation-related gene ontology biological process terms. In contrast, both young and mature hepLal-/- mice displayed only minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy metabolic alterations observed in mice globally lacking LAL. These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to NAFLD. Our study highlights the importance of LAL in maintaining liver homeostasis and demonstrates the drastic consequences of its global deficiency on the liver proteome and liver function.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.