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

Branislav Radović,Nemanja Vujić,Tobias Madl,Saša Frank,Ernst Steyrer,Tamara Tomin,Christina Leopold,Martin Wegscheider,Melanie Korbelius,Dagmar Kolb,Madeleine Goeritzer,Stefanie Schlager,Christoph Magnes,Wolfgang F Graier,Matthias Schittmayer,Jay V Patankar,Hong Du,Clemens Diwoky,Dagmar Kratky,Julia Reindl,Ruth Birner‐Gruenberger ,Lukas N Groschner

doi:10.1007/s00125-016-3968-6

Abstract

Aims/hypothesisLysosomal 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).MethodsWe studied metabolic adaptations in Lal-/- mice.ResultsDespite 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/interpretationOur 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3968-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Highlights

Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters (CE) and triacylglycerols (TG), delivered to the lysosome mainly via LDL particle uptake [1], to release mono- and diacylglycerols and mobilise cholesterol and NEFA for membrane assembly, steroidogenesis and energy production
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
Decreased acyl-CoA concentrations and peroxisome proliferator-activated receptor α signalling in Lal-/- liver We observed severe accumulation of total cholesterol (TC)

Summary

Introduction

Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters (CE) and triacylglycerols (TG), delivered to the lysosome mainly via LDL particle uptake [1], to release mono- and diacylglycerols and mobilise cholesterol and NEFA for membrane assembly, steroidogenesis and energy production. Genetic mutations of human LAL ( known as LIPA) cause an autosomal recessive lysosomal storage disorder with accumulation of CE predominantly in hepatocytes, adrenal glands, intestine and cells of the monocyte-macrophage system throughout the body [2]. Mutations in LAL cause Wolman disease (WD) or cholesteryl ester storage disease (CESD) [3,4,5]. CESD patients have up to 5% residual LAL activity [8], which keeps the syndrome mostly unrecognised until adulthood. These patients suffer from progressive lysosomal CE and TG accumulations, which lead to the characteristic liver pathology and elevated concentrations of serum transaminases, serum LDL and TG. Premature death of individuals with CESD is due to liver failure and/or accelerated atherosclerosis rather than to chronic hyperlipidaemia [2, 9, 10]

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