Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice

Diabetologia. 2016 Aug;59(8):1743-52. doi: 10.1007/s00125-016-3968-6. Epub 2016 May 6.


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.

Keywords: Glucose tolerance; Lipolysis; Lysosomes; VLDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol, VLDL / genetics
  • Cholesterol, VLDL / metabolism*
  • Female
  • Glucose / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Lipolysis / genetics
  • Lipolysis / physiology
  • Liver / metabolism
  • Lysosomes / metabolism
  • Male
  • Mice
  • Sterol Esterase / deficiency
  • Sterol Esterase / genetics
  • Sterol Esterase / metabolism*
  • Triglycerides / metabolism


  • Cholesterol, VLDL
  • Triglycerides
  • Sterol Esterase
  • Glucose