Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice

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 [3H]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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3968-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

ATGL/CGI-58-Dependent Hydrolysis of a Lipid Storage Pool in Murine Enterocytes

“…Within enterocytes, cLD catabolism can also be conducted by lysosomal lipolysis. Because LAL affects VLDL synthesis in the liver (Radović et al, 2016), lysosomal acid lipase (LAL) might be a potential candidate for supplying lipid precursors for CM synthesis, rather than ATGL and CGI-58.…”

Acetyl-CoA carboxylase 1–dependent lipogenesis promotes autophagy downstream of AMPK

“…500 μl of NMR buffer in D 2 O were added to the dried samples, redissolved, and transferred to 5-mm NMR tubes. Metabolites were measured as described previously (95, 96) and detailed below. All NMR experiments were performed at 310 K on a Bruker Avance III 500-MHz spectrometer equipped with a TXI probe head.…”

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target

“…Lal -/mice present with a massive accumulation of TG and CE in the liver, the spleen, the small intestine and the adrenals, which is associated to the loss of white (WAT) and brown adipose tissues (BAT) [30]. Despite the appearance of hepatic foamy lysosomes, lal -/mice show an improved insulin sensitivity and glucose metabolism [31], paralleled by a shift of lipid storage from hepatocytes to Kupffer cells over time [30]. This profile mirrors the observations in hepatic biopsies of LAL deficient patients (discussed below) [11].…”