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 activ...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523001001 |
| _version_ | 1797676713086287872 |
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| author | Ivan Bradić Laura Liesinger Katharina B. Kuentzel Nemanja Vujić Michael Trauner Ruth Birner-Gruenberger Dagmar Kratky |
| author_facet | Ivan Bradić Laura Liesinger Katharina B. Kuentzel Nemanja Vujić Michael Trauner Ruth Birner-Gruenberger Dagmar Kratky |
| author_sort | Ivan Bradić |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T22:33:21Z |
| format | Article |
| id | doaj.art-cec401c7277a49c99853dc84748bd3d0 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-11T22:33:21Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-cec401c7277a49c99853dc84748bd3d02023-09-23T05:09:48ZengElsevierJournal of Lipid Research0022-22752023-09-01649100427Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipaseIvan Bradić0Laura Liesinger1Katharina B. Kuentzel2Nemanja Vujić3Michael Trauner4Ruth Birner-Gruenberger5Dagmar Kratky6Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, AustriaInstitute of Chemical Technologies and Analytics, TU Wien, Vienna, AustriaDivision of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, AustriaDivision of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaInstitute of Chemical Technologies and Analytics, TU Wien, Vienna, Austria; BioTechMed-Graz, Graz, Austria; Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria; For correspondence: Dagmar Kratky; Ruth Birner-GruenbergerDivision of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria; For correspondence: Dagmar Kratky; Ruth Birner-GruenbergerLysosomal 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.http://www.sciencedirect.com/science/article/pii/S0022227523001001lysosomal storage disorderlipid metabolismcholesterolnon-alcoholic fatty liver diseaselipase/lysosomallipids |
| spellingShingle | Ivan Bradić Laura Liesinger Katharina B. Kuentzel Nemanja Vujić Michael Trauner Ruth Birner-Gruenberger Dagmar Kratky Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase Journal of Lipid Research lysosomal storage disorder lipid metabolism cholesterol non-alcoholic fatty liver disease lipase/lysosomal lipids |
| title | Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase |
| title_full | Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase |
| title_fullStr | Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase |
| title_full_unstemmed | Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase |
| title_short | Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase |
| title_sort | metabolic changes and propensity for inflammation fibrosis and cancer in livers of mice lacking lysosomal acid lipase |
| topic | lysosomal storage disorder lipid metabolism cholesterol non-alcoholic fatty liver disease lipase/lysosomal lipids |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523001001 |
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