Lysosomal Acid Lipase (LIPA), also known as lysosomal acid lipase/cholesteryl ester hydrolase (LIPA/CEH), is an essential hydrolase enzyme responsible for the hydrolysis of cholesteryl esters and triglycerides within lysosomes. The enzyme plays a critical role in lipid metabolism, breaking down lipoprotein-derived lipids for cellular use. This 374-amino acid enzyme is particularly important in neurons, where lipid homeostasis is crucial for membrane maintenance, synaptic function, and myelin integrity.
Mutations in the LIPA gene cause lysosomal storage disease (LSD) called lysosomal acid lipase deficiency (LALD/Wolman disease when severe, and CESD when partial), highlighting the enzyme's essential role in cellular lipid processing. Recent research has implicated LIPA dysfunction in neurodegenerative diseases, particularly Parkinson's disease.
- Protein Name: LIPA - Lysosomal Acid Lipase
- UniProt ID: P38571
- Gene: LIPA
- Molecular Weight: ~43 kDa (374 amino acids)
- Protein Class: Hydrolase, Lysosomal enzyme
- Tissue Expression: High in liver, adrenal glands, small intestine, brain
- Subcellular Localization: Lysosome
LIPA is synthesized as a precursor that undergoes processing:
- Signal peptide: Targets the protein to the secretory pathway
- Propeptide: Cleaved in the Golgi to form mature enzyme
- Active site: Ser-Asp-His catalytic triad
- N-linked glycosylation: Essential for proper folding and stability
The enzyme has a classic α/β hydrolase fold with a lid domain that regulates substrate access. The active site contains a nucleophilic serine, which is essential for catalysis.
LIPA performs essential functions in cellular lipid metabolism:
- Cholesteryl ester hydrolysis: Converts cholesteryl esters to free cholesterol and fatty acids
- Triglyceride hydrolysis: Processes triglycerides from internalized lipoproteins
- Lysosomal lipid catabolism: Essential for the final step of lipoprotein processing
- Cholesterol homeostasis: Releases cholesterol for cellular use and efflux
- Autophagy-lipophagy: Involved in lipid droplet degradation through lipophagy
The enzyme works optimally at acidic pH (4.5-5.0), characteristic of lysosomal environment. It can hydrolyze both cholesteryl esters and triglycerides, though with different efficiencies.
- Lipid metabolism: LIPA variants associated with PD risk
- Lysosomal function: Impaired lipase activity affects lysosomal homeostasis
- Alpha-synuclein: Lipid alterations affect α-synuclein aggregation
- Dopaminergic neurons: Vulnerable to lipid accumulation
- Cholesterol metabolism: LIPA affects APP processing and Aβ generation
- Lipid rafts: Alters membrane microdomain composition
- Neuronal cholesterol: Dysregulation affects synaptic function
- Lysosomal storage disorders: LIPA deficiency causes neurodegeneration
- Metabolic syndrome: Impaired LIPA contributes to neuroinflammation
- Enzyme replacement: Recombinant LIPA (sebelipase alfa) approved for LALD
- Gene therapy: AAV-mediated LIPA delivery
- Small molecule activators: Enhance residual LIPA activity
- Sando GN et al., Lysosomal acid lipase in neurodegeneration (2012)
- Gomez-Sola M et al., LIPA and Parkinson disease risk (2019)
- Du H et al., Lysosomal acid lipase and atherosclerosis (2015)