ArticleDiabetologia2016
Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.
Article in Diabetologia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
- Secreted enzyme uptake masks the in vivo phenotype of macrophage-specific lysosomal acid lipase deletion.Molecular metabolism · 2026Article
- Cytosolic Versus Lysosomal Lipolysis in Adipose Tissue: Opposing Roles in Cardiometabolic Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer.Communications medicine · 2025Article
- Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.The Journal of clinical investigation · 2025Article
- Autophagy-lysosome pathway in insulin & glucagon homeostasis.Frontiers in endocrinology · 2025Review
- Loss or inhibition of lysosomal acid lipaseBBA advances · 2025Article
- A crucial role of adenosine deaminase in regulating gluconeogenesis in mice.The Journal of biological chemistry · 2024Article
- Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.Molecular metabolism · 2024Article
- Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice.Gastro hep advances · 2024Article
- Recent insights into lysosomal acid lipase deficiency.Trends in molecular medicine · 2023Review
- Targeting the lysosome: Mechanisms and treatments for nonalcoholic fatty liver disease.Journal of cellular biochemistry · 2022Review
- Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases.Molecular metabolism · 2022Article
- Article
- Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease.Frontiers in genetics · 2022Review
- Lipolysis: cellular mechanisms for lipid mobilization from fat stores.Nature metabolism · 2021Review
- Article
- Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth.International journal of molecular sciences · 2021Article
- Article
- Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2021Article
- Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.Science translational medicine · 2020Article
Corrections and comments
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Authors and funding
22 authors at 7 institutions in 5 countries.
Funding
Abstract
aims/hypothesisLysosomal 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).
methodsWe studied metabolic adaptations in Lal (-/-) mice.
resultsDespite 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/
interpretationOur 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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Registered trials
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