Hepatocyte-specific deletion of lysosomal acid lipase leads to cholesteryl ester but not triglyceride or retinyl ester accumulation.

Autor:	Pajed L; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Wagner C; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Taschler U; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Schreiber R; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Kolleritsch S; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Fawzy N; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Pototschnig I; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Schoiswohl G; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Pusch LM; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II., Wieser BI; the Diagnostic and Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz., Vesely P; the Diagnostic and Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz., Hoefler G; the Diagnostic and Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz.; BioTechMed-Graz, 8010 Graz, Austria., Eichmann TO; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II.; the Center for Explorative Lipidomics, BioTechMed-Graz, and., Zimmermann R; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II.; BioTechMed-Graz, 8010 Graz, Austria., Lass A; From the Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstrasse 31/II, achim.lass@uni-graz.at.; BioTechMed-Graz, 8010 Graz, Austria.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Jun 07; Vol. 294 (23), pp. 9118-9133. Date of Electronic Publication: 2019 Apr 25.
DOI:	10.1074/jbc.RA118.007201
Abstrakt:	Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG). Mice globally lacking LAL accumulate CE most prominently in the liver. The severity of the CE accumulation phenotype progresses with age and is accompanied by hepatomegaly and hepatic cholesterol crystal deposition. In contrast, hepatic TG accumulation is much less pronounced in these mice, and hepatic RE levels are even decreased. To dissect the functional role of LAL for neutral lipid ester mobilization in the liver, we generated mice specifically lacking LAL in hepatocytes (hep-LAL-ko). On a standard chow diet, hep-LAL-ko mice exhibited increased hepatic CE accumulation but unaltered TG and RE levels. Feeding the hep-LAL-ko mice a vitamin A excess/high-fat diet (VitA/HFD) further increased hepatic cholesterol levels, but hepatic TG and RE levels in these mice were lower than in control mice. Performing in vitro activity assays with lysosome-enriched fractions from livers of mice globally lacking LAL, we detected residual acid hydrolytic activities against TG and RE. Interestingly, this non-LAL acid TG hydrolytic activity was elevated in lysosome-enriched fractions from livers of hep-LAL-ko mice upon VitA/HFD feeding. In conclusion, the neutral lipid ester phenotype in livers from hep-LAL-ko mice indicates that LAL is limiting for CE turnover, but not for TG and RE turnovers. Furthermore, in vitro hydrolase activity assays revealed the existence of non-LAL acid hydrolytic activities for TG and RE. The corresponding acid lipase(s) catalyzing these reactions remains to be identified. (© 2019 Pajed et al.)
Databáze:	MEDLINE
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