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Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.
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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.
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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 |
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Fig5: Reduced scWAT and plasma leptin concentrations in Lal-/- mice. (a) H&E staining of inguinal scWAT sections. (b) scWAT mass normalised to BW (n = 6). (c) mRNA expression of leptin (Lep) and adiponectin (Adipoq) in scWAT (n = 4–5). Plasma concentrations of (d) leptin and (e) adiponectin (n = 6). mRNA expression of the receptors of hepatic leptin (Leptr) and adiponectin (Adipor) in (f) fed and (g) 12 h fasted WT and Lal-/- mice (n = 3–5). Data represent means ± SD; *p < 0.05, **p ≤ 0.01; ***p ≤ 0.001, Student’s unpaired t test. Mice were aged 12–16 weeks. Black bars, WT mice; white bars, Lal-/- mice Mentions: Despite comparable food intake, Lal-/- mice were lighter and gained less weight (ESM Fig. 3a, b). They lacked visceral fat and exhibited markedly reduced subcutaneous (sc) WAT at the age of 4 and 12 weeks (ESM Fig. 3c). H&E staining of scWAT sections revealed smaller adipocytes with reduced fat content (Fig. 5a) and we observed reduced inguinal scWAT mass (Fig. 5b) in Lal-/- mice. Adipose tissue fundamentally influences systemic insulin sensitivity and glucose metabolism via the adipokines leptin and adiponectin [23]. Leptin mRNA expression was significantly decreased in scWAT of Lal-/- compared with WT mice, whereas adiponectin mRNA expression was unchanged (Fig. 5c). Since fasting significantly decreases basal leptin levels [24], decreased plasma leptin concentrations (84%) in fed Lal-/- mice but comparable levels as WT mice after fasting (Fig. 5d) indicate that feeding is ineffective to increase the satiety hormone leptin in Lal-/- mice. Plasma adiponectin levels were comparable between both genotypes (Fig. 5e). mRNA expression of the leptin receptors (Leptr)1 and 2 were markedly increased in livers of fed (Fig. 5f) and fasted (Fig. 5g) Lal-/- mice. Expression of adiponectin receptor (Adipor)1 mRNA was higher and expression of Adipor2 mRNA was lower in livers of fed Lal-/- mice than WT fed mice (Fig. 5f). While Adipor1 mRNA levels were similar in fasted livers of both genotypes, transcript levels of Adipor2 were reduced in livers of Lal-/- mice compared with WT livers (Fig. 5g).Fig. 5 |
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.
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.
