title: Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.
abstract: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s).
  
  
  
  We studied metabolic adaptations in Lal (-/-) mice.
  
  
  
  Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels.
  
  
  
  Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radović
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujić
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.|Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Korbelius
authors.affiliation: Center for Medical Research/Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Reindl
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Wegscheider
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.|Omics Center Graz, BioTechMed-Graz, Graz, Austria.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tomin
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.|Omics Center Graz, BioTechMed-Graz, Graz, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birner-Gruenberger
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.|Omics Center Graz, BioTechMed-Graz, Graz, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schittmayer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.|Center for Neural Circuits and Behaviour, University of Oxford, Oxford, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Groschner
authors.affiliation: Health, Bioanalytik und Metabolomics, Joanneum Research, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: Institute of Biomedical Engineering, Graz University of Technology, Graz, Austria.|Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Diwoky
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Saša
authors.initials: S
authors.lastname: Frank
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Steyrer
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.|Omics Center Graz, BioTechMed-Graz, Graz, Austria.|Department of Chemistry, Technical University, Munich, Germany.|Institute of Structural Biology, Helmholtz Zentrum, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria. dagmar.kratky@medunigraz.at.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D015243:Cholesterol, VLDL / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008066:Lipolysis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D002787:Sterol Esterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D015243:Cholesterol, VLDL; D014280:Triglycerides; D002787:Sterol Esterase; D005947:Glucose
keywords: Glucose tolerance; Lipolysis; Lysosomes; VLDL