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

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 - Diabetologia (2016)

Bottom Line: 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.We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Intact mitochondria and reduced ATP concentrations in Lal-/- livers. (a) Electron micrographs of mitochondria in livers of WT and Lal-/- mice aged 12 weeks; scale bar, 0.5 μm. (b) Mitochondrial respiration of mitochondria isolated from WT and Lal-/- livers (n = 4–6) using 10 mmol/l succinate/1 μmol/l rotenone as substrates. Oxygen consumption rate presented as basal mitochondrial respiration in the presence of substrates (basal), increased mitochondrial respiration due to ADP supply (state 3), after ATP synthase inhibition by oligomycin (state 4o) and after carbonyl cyanide p-trifluoromethoxyphenylhydrazone addition (uncoupled). (c) Liver ATP concentrations determined by liquid chromatography-tandem mass spectrometry (n = 5–6 mice aged 8–12 weeks). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, Student’s unpaired t test. Black bars, WT mice; white bars, Lal-/- mice. OCR, oxygen consumption rate
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Fig2: Intact mitochondria and reduced ATP concentrations in Lal-/- livers. (a) Electron micrographs of mitochondria in livers of WT and Lal-/- mice aged 12 weeks; scale bar, 0.5 μm. (b) Mitochondrial respiration of mitochondria isolated from WT and Lal-/- livers (n = 4–6) using 10 mmol/l succinate/1 μmol/l rotenone as substrates. Oxygen consumption rate presented as basal mitochondrial respiration in the presence of substrates (basal), increased mitochondrial respiration due to ADP supply (state 3), after ATP synthase inhibition by oligomycin (state 4o) and after carbonyl cyanide p-trifluoromethoxyphenylhydrazone addition (uncoupled). (c) Liver ATP concentrations determined by liquid chromatography-tandem mass spectrometry (n = 5–6 mice aged 8–12 weeks). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, Student’s unpaired t test. Black bars, WT mice; white bars, Lal-/- mice. OCR, oxygen consumption rate

Mentions: Since insufficient supply of NEFA and, consequently, acyl-CoA may affect mitochondrial function and energy production, we next investigated the hepatic mitochondria of Lal-/- mice. Unaltered mitochondrial morphology (Fig. 2a) and a comparable amount of mitochondrial DNA (ESM Fig. 1a) indicated functional mitochondria. The respiratory capacity of mitochondria isolated from Lal-/- livers was decreased only for the uncoupled state when succinate was provided as substrate (Fig. 2b) but unaltered with glutamate in the presence of malate (ESM Fig. 1b) or pyruvate (ESM Fig. 1c). These data suggest that the lack of substrate (acyl-CoA) might be responsible for reduced ATP concentrations in Lal-/- livers (Fig. 2c).Fig. 2


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

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 - Diabetologia (2016)

Intact mitochondria and reduced ATP concentrations in Lal-/- livers. (a) Electron micrographs of mitochondria in livers of WT and Lal-/- mice aged 12 weeks; scale bar, 0.5 μm. (b) Mitochondrial respiration of mitochondria isolated from WT and Lal-/- livers (n = 4–6) using 10 mmol/l succinate/1 μmol/l rotenone as substrates. Oxygen consumption rate presented as basal mitochondrial respiration in the presence of substrates (basal), increased mitochondrial respiration due to ADP supply (state 3), after ATP synthase inhibition by oligomycin (state 4o) and after carbonyl cyanide p-trifluoromethoxyphenylhydrazone addition (uncoupled). (c) Liver ATP concentrations determined by liquid chromatography-tandem mass spectrometry (n = 5–6 mice aged 8–12 weeks). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, Student’s unpaired t test. Black bars, WT mice; white bars, Lal-/- mice. OCR, oxygen consumption rate
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Intact mitochondria and reduced ATP concentrations in Lal-/- livers. (a) Electron micrographs of mitochondria in livers of WT and Lal-/- mice aged 12 weeks; scale bar, 0.5 μm. (b) Mitochondrial respiration of mitochondria isolated from WT and Lal-/- livers (n = 4–6) using 10 mmol/l succinate/1 μmol/l rotenone as substrates. Oxygen consumption rate presented as basal mitochondrial respiration in the presence of substrates (basal), increased mitochondrial respiration due to ADP supply (state 3), after ATP synthase inhibition by oligomycin (state 4o) and after carbonyl cyanide p-trifluoromethoxyphenylhydrazone addition (uncoupled). (c) Liver ATP concentrations determined by liquid chromatography-tandem mass spectrometry (n = 5–6 mice aged 8–12 weeks). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, Student’s unpaired t test. Black bars, WT mice; white bars, Lal-/- mice. OCR, oxygen consumption rate
Mentions: Since insufficient supply of NEFA and, consequently, acyl-CoA may affect mitochondrial function and energy production, we next investigated the hepatic mitochondria of Lal-/- mice. Unaltered mitochondrial morphology (Fig. 2a) and a comparable amount of mitochondrial DNA (ESM Fig. 1a) indicated functional mitochondria. The respiratory capacity of mitochondria isolated from Lal-/- livers was decreased only for the uncoupled state when succinate was provided as substrate (Fig. 2b) but unaltered with glutamate in the presence of malate (ESM Fig. 1b) or pyruvate (ESM Fig. 1c). These data suggest that the lack of substrate (acyl-CoA) might be responsible for reduced ATP concentrations in Lal-/- livers (Fig. 2c).Fig. 2

Bottom Line: 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.We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.

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.

No MeSH data available.


Related in: MedlinePlus