Browsing by Author "Radović, Branislav"

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    Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice
    (Springer-Verlag, 2016-08) Radović, Branislav; Vujić, Nemanja; Leopold, Christina; Schlager, Stefanie; Goeritzer, Madeleine; Patankar, Jay V.; Korbelius, Melanie; Kolb, Dagmar; Reindl, Julia; Wegscheider, Martin; Tomin, Tamara; Birner-Gruenberger, Ruth; Schittmayer, Matthias; Groschner, Lukas; Magnes, Christoph; Diwoky, Clemens; Frank, Saša; Steyrer, Ernst; Du, Hong; Graier, Wolfgang F.; Madl, Tobias; Kratky, Dagmar; Department of Pathology and Laboratory Medicine, IU School of Medicine
    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.