Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice

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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 [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.

Original languageEnglish (US)
Pages (from-to)1743-1752
Number of pages10
JournalDiabetologia
Volume59
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Sterol Esterase
Insulin Resistance
Peroxisome Proliferator-Activated Receptors
Triglycerides
Glucose
Liver
Acyl Coenzyme A
Skeletal Muscle
Lysosomes
Glycogen
Hepatocyte Nuclear Factor 3-beta
Adipose Tissue
Fenofibrate
Liver Glycogen
Cholesterol Esters
Deoxyglucose
Glucose Tolerance Test
Leptin
Glutamine
Nonesterified Fatty Acids

Keywords

  • Glucose tolerance
  • Lipolysis
  • Lysosomes
  • VLDL

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Radović, B., Vujić, N., Leopold, C., Schlager, S., Goeritzer, M., Patankar, J. V., ... Kratky, D. (2016). Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice. Diabetologia, 59(8), 1743-1752. https://doi.org/10.1007/s00125-016-3968-6

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

In: Diabetologia, Vol. 59, No. 8, 01.08.2016, p. 1743-1752.

Research output: Contribution to journalArticle

Radović, B, Vujić, N, Leopold, C, Schlager, S, Goeritzer, M, Patankar, JV, Korbelius, M, Kolb, D, Reindl, J, Wegscheider, M, Tomin, T, Birner-Gruenberger, R, Schittmayer, M, Groschner, L, Magnes, C, Diwoky, C, Frank, S, Steyrer, E, Du, H, Graier, WF, Madl, T & Kratky, D 2016, 'Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice', Diabetologia, vol. 59, no. 8, pp. 1743-1752. https://doi.org/10.1007/s00125-016-3968-6
Radović B, Vujić N, Leopold C, Schlager S, Goeritzer M, Patankar JV et al. Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice. Diabetologia. 2016 Aug 1;59(8):1743-1752. https://doi.org/10.1007/s00125-016-3968-6
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. / Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice. In: Diabetologia. 2016 ; Vol. 59, No. 8. pp. 1743-1752.
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AU - Radović, Branislav

AU - Vujić, Nemanja

AU - Leopold, Christina

AU - Schlager, Stefanie

AU - Goeritzer, Madeleine

AU - Patankar, Jay V.

AU - Korbelius, Melanie

AU - Kolb, Dagmar

AU - Reindl, Julia

AU - Wegscheider, Martin

AU - Tomin, Tamara

AU - Birner-Gruenberger, Ruth

AU - Schittmayer, Matthias

AU - Groschner, Lukas

AU - Magnes, Christoph

AU - Diwoky, Clemens

AU - Frank, Saša

AU - Steyrer, Ernst

AU - Du, Hong

AU - Graier, Wolfgang F.

AU - Madl, Tobias

AU - Kratky, Dagmar

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N2 - 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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