Modified Low Density Lipoproteins Decrease the Activity and Expression of Lysosomal Acid Lipase in Human Endothelial and Smooth Muscle Cells

Abstract

Lysosomal acid lipase (LAL), the only lysosomal enzyme involved in the hydrolysis of LDL-cholesteryl esters, is a key regulator of cellular cholesterol and fatty acid homeostasis and its deficiency contributes to the pathophysiology of various diseases. In this study, we questioned whether oxidized or glycated LDL, a common occurrence in atherosclerosis and diabetes, affect the activity and expression of LAL in vascular endothelial cells (EC) and smooth muscle cells (SMC). LAL activity and expression were assayed in cultured human EC and SMC exposed to oxidized LDL (oxLDL), (±)9-hydroxyoctadecadienoic acid-cholesteryl ester (HODE), glycated LDL (gLDL), or native LDL (nLDL) as control, in the presence or absence of LXR or PPAR-gamma agonists. We found that LAL activity and expression were significantly down regulated by oxLDL and HODE in EC, and by gLDL in SMC. The LXR agonist T0901317 reversed the decreased LAL expression in modified LDL- or HODE-exposed EC (P < 0.001) and in gLDL-exposed SMC, whereas PPAR-gamma agonist rosiglitazone induced a low effect only in EC. In conclusion, modified LDL down regulates LAL expression in human EC and SMC by a process involving the LXR signaling pathway. This is the first demonstration that modified LDL modulate LAL expression, in a cell specific manner.

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

“…36 37 38 OXLAMs, particularly the isomers and enantiomers produced by free radical mediated oxidation,35 39 68 have been mechanistically linked to cardiovascular disease pathogenesis. Mechanisms include inducing the formation of macrophage foam cells41 42; endothelial cell activation43; migration, proliferation, and foam cell formation of vascular smooth muscle cells44 69; and inhibition of lysosomal hydrolysis of low density lipoprotein cholesteryl esters70 (fig 5 ).…”

Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism

“…It has also been demonstrated by Heltianu et al ( 2011 ) that in some cell types LIPA expression increases with liver-X-receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) agonists. LIPA is not known to contain an LXR or PPAR response element in its promoter region.…”

“…Translocation of TFEB to the nucleus and a modest (0.2-fold) upregulation of LIPA also occurred after a 12 h incubation of peritoneal macrophages with oxidized LDL (oxLDL); the TFEB nuclear localization was reduced at 24 h of oxLDL incubation, however, indicating this response of LIPA is likely mild and transient (Emanuel et al, 2014 ). Heltianu et al ( 2011 ) reported no change in LIPA expression in SMCs and a 20% reduction in LIPA expression in endothelial cells incubated with oxLDL for 24 h. Further studies are required to confirm the importance and cell specificity of TFEB-dependent upregulation of LIPA in response to modified forms of LDL and cellular stress induced by excess cell cholesterol.…”

Induction of Lysosomal Biogenesis in Atherosclerotic Macrophages Can Rescue Lipid-Induced Lysosomal Dysfunction and Downstream Sequelae

“…Oxidized LDL can then bind and inactivate cathepsins with high affinity 30 , inactivate other proteases including the NaβGases 31 , and produce a form of apolipoproteinB that is highly resistant to hydrolysis 32, 33 . OxLDL has also been demonstrated in endothelial and smooth muscle cells to inhibit activity and expression of the enzyme crucial to cholesterol ester hydrolysis, lysosomal acid lipase 34 . Most recently, the formation of cholesterol micro-crystals and ensuing disruption of lysosomal integrity has directly been linked to the build-up of oxLDL in the lysosomal compartment 14 .…”