Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase

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 LALrelated 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 inflammationrelated 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 mainproteome and liver function.

Automated summary

Lysosomal acid lipase (LAL) is responsible for degrading cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency and non-alcoholic fatty liver disease (NAFLD). Comprehensive proteomic profiling of mouse livers with systemic or hepatocyte-specific loss of LAL revealed drastic proteome alterations in Lal-/- mice, including dysregulation of metabolism, inflammation, liver fibrosis, and cancer-related proteins. In contrast, hepLal-/- mice showed minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy the metabolic alterations observed in mice lacking LAL globally.