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Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.
Diabetologia 59, 1743-1752 (2016)
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 [3H]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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Glucose Tolerance ; Lipolysis ; Lysosomes ; Vldl
ISSN (print) / ISBN
0012-186X
e-ISSN
1432-0428
Journal
Diabetologia
Quellenangaben
Volume: 59,
Issue: 8,
Pages: 1743-1752
Publisher
Springer
Publishing Place
Berlin ; Heidelberg [u.a.]
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)