Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Bradić, I; Liesinger, L; Kuentzel, KB; Vujić, N; Trauner, M; Birner-Gruenberger, R; Kratky, D.
Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase.
J Lipid Res. 2023; 64(9):100427 Doi: 10.1016/j.jlr.2023.100427 [OPEN ACCESS]
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Leading authors Med Uni Graz

Birner-Grünberger Ruth

Bradic Ivan

Kratky Dagmar

Co-authors Med Uni Graz

Küntzel Katharina Barbara

Liesinger Laura

Trauner Michael

Vujic Nemanja

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Abstract:

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.

Find related publications in this database (using NLM MeSH Indexing)

Mice - administration & dosage

Animals - administration & dosage

Sterol Esterase - genetics, metabolism

Non-alcoholic Fatty Liver Disease - metabolism

Proteome - genetics, metabolism

Proteomics - administration & dosage

Liver - metabolism

Wolman Disease - genetics, metabolism, pathology

Liver Cirrhosis - genetics

Triglycerides - metabolism

Inflammation - metabolism

Neoplasms - metabolism

Find related publications in this database (Keywords)

Supplementary key words lysosomal storage disorder

lipid metabolism

cholesterol

non-alcoholic fatty liver disease

lipase/lysosomal

lipids

liver

proteomics

cholesterol ester storage disease

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