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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

Reduced glycogen, glucose and glutamine concentrations in Lal-/- livers. (a) Plasma glycerol in fasted (n = 5) and (b) liver glycogen concentrations in fed mice (n = 8). (c–f) Glucose concentrations after i.p. injection of (c) glucagon (140 μg/kg BW), (d) glycerol (2 g/kg BW), (e) pyruvate (2 g/kg BW) and (f) glutamine (2 g/kg BW) in plasma of (c) fed and (d–f) fasted mice (n = 5–7). (g) Liver metabolites in fed mice (n = 6). (h) mRNA expression of glucokinase (Gck), phosphofructokinase (Pfkl), fructose-biphosphatase 1 (Fbp1), aldolase B (Aldob), phosphoglycerate kinase 1 (Pgk1), pyruvate kinase 1 (Pk1), glucose-6-phosphate dehydrogenase (G6pd; also known as G6pdx), glycogen phosphorylase (Pygl), glycerol-3-phosphate dehydrogenase1 (Gpd1) and pyruvate dehydrogenase (Pdhb) (n = 6–9). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, ***p ≤ 0.001. (a, b, g, h) Student’s unpaired t test, (c–f) ANOVA. Mice were aged 12–18 weeks. Black bars and squares, WT mice; white bars and squares, Lal-/- mice
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Fig6: Reduced glycogen, glucose and glutamine concentrations in Lal-/- livers. (a) Plasma glycerol in fasted (n = 5) and (b) liver glycogen concentrations in fed mice (n = 8). (c–f) Glucose concentrations after i.p. injection of (c) glucagon (140 μg/kg BW), (d) glycerol (2 g/kg BW), (e) pyruvate (2 g/kg BW) and (f) glutamine (2 g/kg BW) in plasma of (c) fed and (d–f) fasted mice (n = 5–7). (g) Liver metabolites in fed mice (n = 6). (h) mRNA expression of glucokinase (Gck), phosphofructokinase (Pfkl), fructose-biphosphatase 1 (Fbp1), aldolase B (Aldob), phosphoglycerate kinase 1 (Pgk1), pyruvate kinase 1 (Pk1), glucose-6-phosphate dehydrogenase (G6pd; also known as G6pdx), glycogen phosphorylase (Pygl), glycerol-3-phosphate dehydrogenase1 (Gpd1) and pyruvate dehydrogenase (Pdhb) (n = 6–9). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, ***p ≤ 0.001. (a, b, g, h) Student’s unpaired t test, (c–f) ANOVA. Mice were aged 12–18 weeks. Black bars and squares, WT mice; white bars and squares, Lal-/- mice

Mentions: Significantly reduced plasma glycerol concentrations in fasted Lal-/- mice indicate diminished peripheral lipolysis (Fig. 6a). Reduced liver glycogen concentrations in fed Lal-/- mice (Fig. 6b) were confirmed by decreased mobilisation of glucose from glycogen after i.p. injection of glucagon (Fig. 6c). Reduced liver storage of glucose is a result of ineffective production or extensive usage. We therefore determined the ability of Lal-/- mice to produce glucose from different carbon sources. After i.p. injection of glycerol, de novo synthesised glucose reached similar maximal values after 30 min in WT and after 15 min in Lal-/- mice (Fig. 6d). Thus, glucose was cleared faster from the circulation in Lal-/- mice as shown by significantly decreased levels after 60 min, implying increased systemic glucose usage. Gluconeogenesis as measured by pyruvate tolerance test was unaltered (Fig. 6e), but drastically decreased in Lal-/- mice after i.p. injection of glutamine (Fig. 6f). In line, hepatic glucose and glutamine concentrations were markedly reduced in livers of fed Lal-/- mice (Fig. 6g), whereas lactate and pyruvate levels were comparable to those in WT mice. Decreased hepatic glucose content may be a reason why (with the exception of liver-specific phosphofructokinase [Pfkl]) the mRNA expression levels of all other liver enzymes involved in glycolysis were reduced in Lal-/- livers (Fig. 6h).Fig. 6


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)

Reduced glycogen, glucose and glutamine concentrations in Lal-/- livers. (a) Plasma glycerol in fasted (n = 5) and (b) liver glycogen concentrations in fed mice (n = 8). (c–f) Glucose concentrations after i.p. injection of (c) glucagon (140 μg/kg BW), (d) glycerol (2 g/kg BW), (e) pyruvate (2 g/kg BW) and (f) glutamine (2 g/kg BW) in plasma of (c) fed and (d–f) fasted mice (n = 5–7). (g) Liver metabolites in fed mice (n = 6). (h) mRNA expression of glucokinase (Gck), phosphofructokinase (Pfkl), fructose-biphosphatase 1 (Fbp1), aldolase B (Aldob), phosphoglycerate kinase 1 (Pgk1), pyruvate kinase 1 (Pk1), glucose-6-phosphate dehydrogenase (G6pd; also known as G6pdx), glycogen phosphorylase (Pygl), glycerol-3-phosphate dehydrogenase1 (Gpd1) and pyruvate dehydrogenase (Pdhb) (n = 6–9). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, ***p ≤ 0.001. (a, b, g, h) Student’s unpaired t test, (c–f) ANOVA. Mice were aged 12–18 weeks. Black bars and squares, WT mice; white bars and squares, Lal-/- mice
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Related In: Results  -  Collection

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Fig6: Reduced glycogen, glucose and glutamine concentrations in Lal-/- livers. (a) Plasma glycerol in fasted (n = 5) and (b) liver glycogen concentrations in fed mice (n = 8). (c–f) Glucose concentrations after i.p. injection of (c) glucagon (140 μg/kg BW), (d) glycerol (2 g/kg BW), (e) pyruvate (2 g/kg BW) and (f) glutamine (2 g/kg BW) in plasma of (c) fed and (d–f) fasted mice (n = 5–7). (g) Liver metabolites in fed mice (n = 6). (h) mRNA expression of glucokinase (Gck), phosphofructokinase (Pfkl), fructose-biphosphatase 1 (Fbp1), aldolase B (Aldob), phosphoglycerate kinase 1 (Pgk1), pyruvate kinase 1 (Pk1), glucose-6-phosphate dehydrogenase (G6pd; also known as G6pdx), glycogen phosphorylase (Pygl), glycerol-3-phosphate dehydrogenase1 (Gpd1) and pyruvate dehydrogenase (Pdhb) (n = 6–9). Data represent means ± SD; *p < 0.05, **p ≤ 0.01, ***p ≤ 0.001. (a, b, g, h) Student’s unpaired t test, (c–f) ANOVA. Mice were aged 12–18 weeks. Black bars and squares, WT mice; white bars and squares, Lal-/- mice
Mentions: Significantly reduced plasma glycerol concentrations in fasted Lal-/- mice indicate diminished peripheral lipolysis (Fig. 6a). Reduced liver glycogen concentrations in fed Lal-/- mice (Fig. 6b) were confirmed by decreased mobilisation of glucose from glycogen after i.p. injection of glucagon (Fig. 6c). Reduced liver storage of glucose is a result of ineffective production or extensive usage. We therefore determined the ability of Lal-/- mice to produce glucose from different carbon sources. After i.p. injection of glycerol, de novo synthesised glucose reached similar maximal values after 30 min in WT and after 15 min in Lal-/- mice (Fig. 6d). Thus, glucose was cleared faster from the circulation in Lal-/- mice as shown by significantly decreased levels after 60 min, implying increased systemic glucose usage. Gluconeogenesis as measured by pyruvate tolerance test was unaltered (Fig. 6e), but drastically decreased in Lal-/- mice after i.p. injection of glutamine (Fig. 6f). In line, hepatic glucose and glutamine concentrations were markedly reduced in livers of fed Lal-/- mice (Fig. 6g), whereas lactate and pyruvate levels were comparable to those in WT mice. Decreased hepatic glucose content may be a reason why (with the exception of liver-specific phosphofructokinase [Pfkl]) the mRNA expression levels of all other liver enzymes involved in glycolysis were reduced in Lal-/- livers (Fig. 6h).Fig. 6

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