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Diabetologia. 2016 Aug;59(8):1743-52. doi: 10.1007/s00125-016-3968-6. Epub 2016 May 6.

Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.

Author information

1
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.
2
Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
3
Center for Medical Research/Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
4
Institute of Pathology, Medical University of Graz, Graz, Austria.
5
Omics Center Graz, BioTechMed-Graz, Graz, Austria.
6
Center for Neural Circuits and Behaviour, University of Oxford, Oxford, UK.
7
Health, Bioanalytik und Metabolomics, Joanneum Research, Graz, Austria.
8
Institute of Biomedical Engineering, Graz University of Technology, Graz, Austria.
9
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
10
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
11
Department of Chemistry, Technical University, Munich, Germany.
12
Institute of Structural Biology, Helmholtz Zentrum, Munich, Germany.
13
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria. dagmar.kratky@medunigraz.at.

Abstract

AIMS/HYPOTHESIS:

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).

METHODS:

We studied metabolic adaptations in Lal (-/-) mice.

RESULTS:

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.

CONCLUSIONS/INTERPRETATION:

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.

KEYWORDS:

Glucose tolerance; Lipolysis; Lysosomes; VLDL

PMID:
27153842
PMCID:
PMC4930475
DOI:
10.1007/s00125-016-3968-6
[Indexed for MEDLINE]
Free PMC Article

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