Recent insights into lysosomal acid lipase deficiency

Abstract

Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies.

Keywords: LAL-D; LIPA; Wolman disease; acid lipolysis; cholesteryl ester storage disease; lysosomal lipid storage disorder.

Figure 1. Structure of human lysosomal acid lipase (LAL).

Upper panel: chromosomal location of the human LIPA gene and structure of the human LAL protein (residues 22–399, PDB 6v7n) viewed from the front. Lower panel: structural features of human LAL (Uniprot: P38571; 399 amino acids) including the six glycosylation sites, the α/β hydrolase fold, the active triad (Ser-174, Asp-345, His-374) [3], α-helices, and β-strands.

Figure 2. Transcriptional regulation of lysosomal acid lipase (LAL).

Upon nutrient starvation, mTOR inhibition results in the dephosphorylation of transcription factor EB (TFEB), which either directly or indirectly activates LIPA transcription via the peroxisome proliferator-activated receptor α (PPARα)–PPARγ coactivator 1α (PGC1α) cascade. Nutrient deprivation also activates AMP-activated protein kinase (AMPK), leading to activation of sirtuin 1 (SIRT1), phosphorylation of PGC1α, and phosphorylation of the Unc-51-like autophagy activating kinase (ULK1), the latter further activating the autophagic machinery. SIRT1 deacetylates PGC1α and forkhead box protein O1 (FOXO1), which initiate LIPA transcription in the nucleus together with TFEB. In macrophages, modified low-density lipoprotein (LDL) particles like aggregated (agg) or oxidized (ox) LDL inhibit enzymatic activity of the LAL protein, presumably via raising lysosomal pH.

Figure 3. The role of lysosomal acid lipase (LAL)-mediated lipid hydrolysis in cellular lipid homeostasis.

(A) In hepatocytes, low-density lipoproteins (LDLs) internalized by receptor-mediated endocytosis and cytosolic lipid droplets delivered via autophagy are essential sources of triacylglycerols (TGs) and cholesteryl esters (CEs) for lysosomal lipolysis by LAL. In addition, LAL hydrolyzes diacylglycerols (DGs), monoacylglycerols (MGs), and retinyl esters (REs) into free cholesterol (FC), fatty acids (FAs), free glycerol (FG), and retinol (ROH). FAs can either be used for FA oxidation and signaling pathways or become re-esterified to TG for very low-density lipoprotein (VLDL) secretion or storage in cytosolic lipid droplets. FC is exported from the lysosome via Niemann–Pick disease type C (NPC) 1 and 2 proteins and is further used for signaling pathways, storage in lipid droplets, or secretion in HDL particles. (B) Consequences of LAL-D on cellular lipid homeostasis. Absent or dysfunctional LAL results in accumulation of neutral lipids within the lysosome, leading to reduced availability of FC and FA for metabolic pathways. Diminished intracellular FA concentrations activate endogenous FA synthesis to maintain VLDL secretion. In turn, decreased availability of FC activates de novo cholesterol synthesis and stimulates LDL receptor (LDLR) expression to increase intracellular cholesterol concentrations. Abbreviation: SREBP, sterol regulatory element-binding protein.

Figure 4. Main characteristics of lysosomal acid lipase deficiency (LAL-D).

(A) Biochemical and clinical characteristics of early- and late-onset LAL-D. (B) Clinical consequences of LAL-D. Mutations in the LIPA gene leading to enzymatic dysfunction of LAL cause lysosomal accumulation of neutral lipids, predominantly in liver and macrophages. Summary of systemic, hepatic, intestinal, and splenic symptoms associated with LAL-D. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CE, cholesteryl ester; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triacylglycerol.

Figure 5. Potential problems of statin treatment in lysosomal acid lipase deficiency (LAL-D) patients.

In addition to the enzymatic dysfunction and the associated accumulation of cholesteryl esters in the lysosome but lower intracellular concentrations of free cholesterol (FC) in LAL-D, statin treatment further reduces the intracellular availability of FC. This creates a vicious cycle in which the cell tries in vain to maintain cholesterol homeostasis. ① Statin treatment inhibits de novo cholesterol synthesis through blocking the rate-limiting enzyme HMG-CoA reductase (HMGCR). ② Reduced cholesterol availability attenuates very-low-density lipoprotein (VLDL) secretion and lowers circulating cholesterol levels. ③ Decreased cellular cholesterol levels also lead to activation of sterol-regulatory element-binding protein 2 (SREBP2) and compensatory upregulation of HMGCR to sustain cellular cholesterol homeostasis, but this is inhibited by statins. ④ In addition, activation of SREBP2 results in increased low-density lipoprotein receptor (LDLR) synthesis, causing ⑤ increased clearance of LDL from the circulation and uptake of LDL by the liver. ⑥ Endocytosed LDL remains entrapped within the lysosome and exacerbates hepatic lipid deposition and liver disease in LAL-D.