Dataset Information

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

ABSTRACT: 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).We studied metabolic adaptations in Lal (-/-) mice.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 ? (PPAR?) target genes. However, treatment of Lal (-/-) mice with the PPAR? agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4? 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.Our findings indicate that neither activation nor inactivation of PPAR? 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.

SUBMITTER: Radovic B

PROVIDER: S-EPMC4930475 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Radović Branislav B Vujić Nemanja N Leopold Christina C Schlager Stefanie S Goeritzer Madeleine M Patankar Jay V JV Korbelius Melanie M Kolb Dagmar D Reindl Julia J Wegscheider Martin M Tomin Tamara T Birner-Gruenberger Ruth R Schittmayer Matthias M Groschner Lukas L Magnes Christoph C Diwoky Clemens C Frank Saša S Steyrer Ernst E Du Hong H Graier Wolfgang F WF Madl Tobias T Kratky Dagmar D

Diabetologia 20160506 8

<h4>Aims/hypothesis</h4>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).<h4>Methods</h4>We studied metabolic adaptations in Lal (-/-) mice.<h4>Results</h4>Despite loss of adipose tissue, Lal (-/-) ...[more]

PMID: 27153842

Similar Datasets

Project description:BackgroundPPARs (?,?,?) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Methods/principal findingsUsing PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL?LDL, IDL) to activate PPAR? preferentially over PPAR? or PPAR?, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPAR? in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPAR? target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPAR? activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPAR? activation and ADRP gene regulation in vitro.ConclusionsThese data define a novel pathway involving HL hydrolysis of VLDL that activates PPAR? through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets