LIPA

Summary

LIPA (lipase A, lysosomal acid type, HGNC:6617) is a protein-coding gene on chromosome 10q23.31, encoding Lysosomal acid lipase/cholesteryl ester hydrolase (P38571). Catalyzes the deacylation of cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.

This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 3988 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lysosomal acid lipase deficiency (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 796 total — 63 pathogenic, 86 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_000235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6617
Approved symbol	LIPA
Name	lipase A, lysosomal acid type
Location	10q23.31
Locus type	gene with protein product
Status	Approved
Aliases	LAL, CESD
Ensembl gene	ENSG00000107798
Ensembl biotype	protein_coding
OMIM	613497
Entrez	3988

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 35 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000282673, ENST00000336233, ENST00000371837, ENST00000428800, ENST00000456827, ENST00000463623, ENST00000487618, ENST00000489359, ENST00000868661, ENST00000868662, ENST00000868663, ENST00000868664, ENST00000868665, ENST00000868666, ENST00000868667, ENST00000868668, ENST00000868669, ENST00000868670, ENST00000868671, ENST00000868672, ENST00000868673, ENST00000868674, ENST00000868675, ENST00000868676, ENST00000868677, ENST00000868678, ENST00000868680, ENST00000868682, ENST00000868683, ENST00000868685, ENST00000868687, ENST00000938131, ENST00000938132, ENST00000938133, ENST00000938134, ENST00000949400, ENST00000949401, ENST00000949402

RefSeq mRNA: 3 — MANE Select: NM_000235 NM_000235, NM_001127605, NM_001288979

CCDS: CCDS73160, CCDS7401

Canonical transcript exons

ENST00000336233 — 10 exons

Exon	Start	End
ENSE00000712971	89245676	89245793
ENSE00000986519	89225092	89225228
ENSE00000986520	89223684	89223830
ENSE00001142216	89247538	89247649
ENSE00001371258	89222511	89222582
ENSE00001950352	89251737	89251775
ENSE00002462771	89226895	89227004
ENSE00003291124	89215938	89216009
ENSE00003731800	89228200	89228398
ENSE00003850751	89213572	89215061

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 204.8995 / max 12663.0592, expressed in 1767 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110571	104.6139	1703
110572	92.1012	1764
110581	3.2729	218
110585	1.4417	236
110587	0.9813	514
110588	0.5471	189
110558	0.3484	110
110556	0.3182	96
110559	0.3050	132
110568	0.2286	95

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.76	gold quality
duodenum	UBERON:0002114	98.72	gold quality
corpus callosum	UBERON:0002336	98.72	gold quality
visceral pleura	UBERON:0002401	98.32	gold quality
monocyte	CL:0000576	98.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.30	gold quality
mononuclear cell	CL:0000842	98.28	gold quality
inferior vagus X ganglion	UBERON:0005363	98.24	gold quality
leukocyte	CL:0000738	98.17	gold quality
spinal cord	UBERON:0002240	98.06	gold quality
spleen	UBERON:0002106	97.96	gold quality
trabecular bone tissue	UBERON:0002483	97.66	gold quality
lymph node	UBERON:0000029	97.63	gold quality
pleura	UBERON:0000977	97.51	gold quality
subthalamic nucleus	UBERON:0001906	97.47	gold quality
gall bladder	UBERON:0002110	97.30	gold quality
middle frontal gyrus	UBERON:0002702	97.21	gold quality
parietal pleura	UBERON:0002400	97.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.90	gold quality
germinal epithelium of ovary	UBERON:0001304	96.73	gold quality
lateral globus pallidus	UBERON:0002476	96.72	gold quality
pons	UBERON:0000988	96.65	gold quality
skin of hip	UBERON:0001554	96.63	gold quality
synovial joint	UBERON:0002217	96.57	gold quality
rectum	UBERON:0001052	96.49	gold quality
bronchial epithelial cell	CL:0002328	96.44	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.44	gold quality
lower lobe of lung	UBERON:0008949	96.39	gold quality
adrenal tissue	UBERON:0018303	96.35	gold quality
adult organism	UBERON:0007023	96.31	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	4074.02
E-MTAB-7407	yes	3018.26
E-MTAB-8495	yes	1759.57
E-ANND-5	yes	649.92
E-MTAB-10553	yes	34.88
E-HCAD-9	yes	23.40
E-CURD-112	yes	17.92
E-ANND-3	yes	12.89
E-MTAB-7381	no	538.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, NR5A1, PLCG2, SP1, TFAP2A, TREM2

miRNA regulators (miRDB)

123 targeting LIPA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 40)

• macrophage cholesteryl ester hydrolase associates with its intracellular substrate (lipid droplets) and hydrolyzes cholesteryl esters more efficiently from mixed droplets (PMID:16024911)
• The human liver enzyme is expressed in hepatocytes, where it potentially regulates the synthesis of bile acids and thus the removal of cholesterol from the body. (PMID:16131527)
• Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis. (PMID:18796546)
• the molecular characterization of three heterozygous patients with Cholesteryl Ester Storage Disease carrying the common LIPA gene mutation (c.894 G>A, del p.S275_Q298), in combination with two novel mutations resulting in null alleles, was reported. (PMID:19307143)
• Lysosomal acid lipase in myeloid cells plays a critical role in maintaining normal hematopoietic cell development and balancing immunosuppression and inflammation. (PMID:21900179)
• a novel paternally inherited c.482delA mutation in exon 5 of Lipase A that results in a frameshift mutation at amino acid 161 is reported in a fatal case of Wolman disease (PMID:21963785)
• study identified two novel mutations of LIPA gene in Wolman Disease patients which abolished the expression of LAL enzyme; also found that all cholesteryl ester storage disease patients carried the common mutant allele c.894G>A (PMID:22227072)
• LIPA polymorphisms contribute to the interindividual variability observed in obesity-related metabolic complications (PMID:22395809)
• The results show that lysosomal acid lipase E8SJM mutation carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype. (PMID:22795295)
• The expression of LIPA may be associated with increased phospholipid content in the brains of violent suicide completers. (PMID:23164340)
• CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies. CESD may be underdiagnosed in the general Caucasian and Hispanic populations. (PMID:23424026)
• used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency (PMID:23624251)
• Mutations in lysosomal acid lipase A result in two phenotypes depending on the extent of lysosomal acid lipase deficiency. [Review] (PMID:23652569)
• the rs1412444 and rs2246833 of the LIPA gene are shared susceptibility polymorphisms for CAD among different ethnicities. (PMID:24069331)
• To our knowledge, this is the first pediatric case of genetically and biopsy confirmed CESD without hepatomegaly, suggesting that this diagnosis can be easily missed. (PMID:24122380)
• Wolmans disease is a rare autosomal recessive lysosomal storage disease. (PMID:24832708)
• The observed loss-of-function phenotype in cholesteryl ester storage disease patients with the His295Tyr (H295Y) mutation in the LAL gene might arise from a combination of protein destabilization and the shift to a non-functional soluble aggregate. (PMID:25620107)
• Case Report: Mexican sisters with heterozygous mutations in exon 4: c.253C>A and c.294C>G resulting in lysosomal acid lipase deficiency. (PMID:25624737)
• lysosomal acid lipase in hepatocytes is a critical metabolic enzyme in controlling neutral lipid metabolism (PMID:26212911)
• These findings suggest a strong association between impaired LAL activity and Non-alcoholic fatty liver disease. (PMID:26288848)
• Study demonstrates that liver cirrhosis from any etiology is characterized by a significant reduction of LAL activity but no known c.894G>A SNP, which is likely on an acquired base and independent from the etiology of hepatic disease. (PMID:27219619)
• results indicate that LAL is the major acid RE hydrolase and required for functional retinoid homeostasis. (PMID:27354281)
• LIPA mutations may have a role in with a clinical diagnosis of familial hypercholesterolemia (PMID:27423329)
• LAL plays a critical role in regulating mesenchymal stem cells’ ability to stimulate tumor growth and metastasis, which provides a mechanistic basis for targeting LAL in MSCs to reduce the risk of cancer metastasis (PMID:27531897)
• Coronary artery disease-associated coding variant rs1051338 causes reduced lysosomal LAL protein and activity because of increased LAL degradation. (PMID:28279971)
• Report a marked reduction of LAL activity in patients with cryptogenic cirrhosis. (PMID:28396038)
• LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. (PMID:28587063)
• Report LIPA variants/phenotype in childhood-onset lysosomal acid lipase deficiency. (PMID:28881270)
• Use CRISPR/Cas9 techniques to knockout LIPA in human induced pluripotent stem cells and differentiate them to macrophages. (PMID:28882870)
• LIPA associated with Familial Hypercholesterolemia and Polygenic Hypercholesterolemia in patients with Acute Coronary Syndrome , age </=65 years, and LDL-C levels >/=160 mg/dl. (PMID:28958330)
• Mutation in the lysosomal acid lipase gene is associated with cholesteryl ester storage disease in hypercholesterolemia. (PMID:29196158)
• Homozygous or compound heterozygous LIPA mutations were identified. Lysosomal acid lipase (LAL) activity in white blood cells is a validated tool for Lysosomal acid lipase deficiency (LAL-D) diagnosis. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations. (PMID:30684275)
• Most pathogenic mutations in LIPA gene (LAL) result in defective enzyme activity by affecting the normal folding of LAL. Nearly all mutations that affect the stability of the core domain result in endoplasmic reticulum (ER) stress. As a consequence, ER stress resulted in ER-associated degradation of the mutant protein. Rescue of mutant proteins by chemical chaperones did not restore enzymatic activity. (PMID:31131398)
• Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency. (PMID:31182375)
• Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non-alcoholic fatty liver disease. (PMID:31392821)
• Patients with non-alcoholic fatty liver disease show a significant, progressive reduction of LAL (LIPA) activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. (PMID:31435171)
• LAL activity is reduced in non-alcoholic fatty liver disease patients, independently from disease progression. In vitro, impaired LAL activity induced by Fatty Acids loading was rescued by PPAR-alpha activation. (PMID:31505261)
• Lysosomal acid lipase deficiency is most common in Caucasians of European descent. It is due to a mutation in the LIPA gene. In North America, the prevalence of CESD is about 0.0008% in Caucasian and Hispanic populations. (PMID:31582009)
• Lysosomal acid lipase does not have a propeptide and should not be considered being a proprotein. (PMID:31587363)
• common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk. (PMID:31645127)

Cross-species orthologs

31 orthologs

Organism	Symbol	Gene ID
danio_rerio	lipf	ENSDARG00000018529
mus_musculus	Lipa	ENSMUSG00000024781
rattus_norvegicus	Lipa	ENSRNOG00000019077
drosophila_melanogaster	Lip3	FBGN0023495
drosophila_melanogaster	Lip1	FBGN0023496
drosophila_melanogaster	Lip2	FBGN0024740
drosophila_melanogaster	CG2772	FBGN0031533
drosophila_melanogaster	Lip4	FBGN0032264
drosophila_melanogaster	CG18301	FBGN0032265
drosophila_melanogaster	CG18302	FBGN0032266
drosophila_melanogaster	CG7329	FBGN0032271
drosophila_melanogaster	CG3635	FBGN0032981
drosophila_melanogaster	CG8093	FBGN0033999
drosophila_melanogaster	CG11406	FBGN0034990
drosophila_melanogaster	mag	FBGN0036996
drosophila_melanogaster	CG11598	FBGN0038067
drosophila_melanogaster	CG11600	FBGN0038068
drosophila_melanogaster	CG11608	FBGN0038069
drosophila_melanogaster	CG6753	FBGN0038070
drosophila_melanogaster	CG18530	FBGN0042207
drosophila_melanogaster	CG18284	FBGN0043825
drosophila_melanogaster	CG31089	FBGN0051089
drosophila_melanogaster	CG31091	FBGN0051091
drosophila_melanogaster	CG31871	FBGN0051871
drosophila_melanogaster	CG31872	FBGN0051872
drosophila_melanogaster	CG17097	FBGN0265264
caenorhabditis_elegans		WBGENE00009773
caenorhabditis_elegans		WBGENE00010062
caenorhabditis_elegans		WBGENE00020016
caenorhabditis_elegans		WBGENE00021963
caenorhabditis_elegans		WBGENE00022642

Paralogs (5): LIPM (ENSG00000173239), LIPF (ENSG00000182333), LIPN (ENSG00000204020), LIPK (ENSG00000204021), LIPJ (ENSG00000204022)

Protein

Protein identifiers

Lysosomal acid lipase/cholesteryl ester hydrolase — P38571 (reviewed: P38571)

Alternative names: Cholesteryl esterase, Diacylglycerol lipase, Lipase A, Sterol esterase, Triacylglycerol ester hydrolase, Triacylglycerol lipase

All UniProt accessions (4): P38571, A0A0A0MT32, Q5T073, Q5T770

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the deacylation of cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol. Hydrolyzes triglycerides (1,2,3-triacylglycerol) and diglycerides (such as 1,2-diacylglycerol and 1,3-diacylglycerol) with preference for the acyl moieties at the sn-1 or sn-3 positions.

Subunit / interactions. Monomer.

Subcellular location. Lysosome.

Tissue specificity. Most abundantly expressed in brain, lung, kidney and mammary gland, a moderate expression seen in placenta and expressed at low levels in the liver and heart.

Post-translational modifications. Glycosylation is not essential for catalytic activity.

Disease relevance. Cholesteryl ester storage disease (CESD) [MIM:278000] An autosomal recessive, mild form of lysosomal acid lipase deficiency characterized by accumulation of cholesteryl esters and triglycerides primarily in the liver. The clinical presentation is highly variable depending on residual levels of lysosomal acid lipase activity, and ranges from early onset of severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood. Age at onset varies from childhood to adulthood. The disease is caused by variants affecting the gene represented in this entry. Wolman disease (WOLD) [MIM:620151] An autosomal recessive, fulminant form of lysosomal acid lipase deficiency manifesting in early infancy. It is characterized by massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. In addition, accumulation of cholesteryl esters in the zona reticularis of the adrenal gland leads to adrenal calcification and cortical insufficiency. Death occurs early in life from inanition. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AB hydrolase superfamily. Lipase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P38571-1	1	yes
P38571-2	2

RefSeq proteins (3): NP_000226, NP_001121077, NP_001275908 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000073	AB_hydrolase_1	Domain
IPR025483	Lipase_euk	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily

Pfam: PF00561

Catalyzed reactions (Rhea), 8 shown:

• a sterol ester + H2O = a sterol + a fatty acid + H(+) (RHEA:10100)
• cholesteryl (9Z-octadecenoate) + H2O = cholesterol + (9Z)-octadecenoate + H(+) (RHEA:33875)
• a triacylglycerol + H2O = a 1,2-diacylglycerol + a fatty acid + H(+) (RHEA:35667)
• 1,2-di-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O (RHEA:38379)
• 1,3-di-(9Z-octadecenoyl)-glycerol + H2O = 1-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:39939)
• 1,2-di-(9Z-octadecenoyl)-glycerol + H2O = 1-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:40967)
• a 1,2-diacylglycerol + H2O = a 1-acylglycerol + a fatty acid + H(+) (RHEA:44712)
• a 1,3-diacylglycerol + H2O = a 1-acylglycerol + a fatty acid + H(+) (RHEA:78019)

UniProt features (63 total): helix 22, strand 13, sequence variant 8, glycosylation site 6, turn 3, splice variant 2, mutagenesis site 2, active site 2, signal peptide 1, propeptide 1, chain 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6V7N	X-RAY DIFFRACTION	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38571-F1	91.87	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 174 (charge relay system); 374 (charge relay system)

Glycosylation sites (6): 273, 321, 36, 72, 101, 161

Mutagenesis-validated functional residues (2):

Position	Phenotype
76	no effect on enzyme activity.
77	significant loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8964038	LDL clearance
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-382551	Transport of small molecules
R-HSA-8964043	Plasma lipoprotein clearance

MSigDB gene sets: 604 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, MODULE_172, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_EXCRETION, GOBP_DIGESTION, MODULE_97, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_GLAND_MORPHOGENESIS, GOBP_LYSOSOMAL_TRANSPORT

GO Biological Process (76): mitotic cell cycle (GO:0000278), cell morphogenesis (GO:0000902), endothelial cell proliferation (GO:0001935), response to dietary excess (GO:0002021), hematopoietic progenitor cell differentiation (GO:0002244), acute inflammatory response (GO:0002526), respiratory burst involved in inflammatory response (GO:0002536), glucose metabolic process (GO:0006006), glycolytic process (GO:0006096), fatty acid metabolic process (GO:0006631), triglyceride metabolic process (GO:0006641), cholesterol biosynthetic process (GO:0006695), ATP biosynthetic process (GO:0006754), vitamin A metabolic process (GO:0006776), endocytosis (GO:0006897), mitochondrion organization (GO:0007005), lysosome organization (GO:0007040), small GTPase-mediated signal transduction (GO:0007264), endosome to lysosome transport (GO:0008333), determination of adult lifespan (GO:0008340), response to cold (GO:0009409), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), cholesterol storage (GO:0010878), lipid catabolic process (GO:0016042), sterol metabolic process (GO:0016125), myeloid cell differentiation (GO:0030099), T cell differentiation (GO:0030217), lung development (GO:0030324), defecation (GO:0030421), TOR signaling (GO:0031929), myeloid cell apoptotic process (GO:0033028), response to vitamin A (GO:0033189), cholesterol efflux (GO:0033344), low-density lipoprotein particle clearance (GO:0034383), common myeloid progenitor cell proliferation (GO:0035726), T cell proliferation (GO:0042098), lipoprotein catabolic process (GO:0042159), spleen development (GO:0048536), bone marrow development (GO:0048539)

GO Molecular Function (5): sterol ester esterase activity (GO:0004771), lipase activity (GO:0016298), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleoplasm (GO:0005654), lysosome (GO:0005764), cytosol (GO:0005829), lysosomal lumen (GO:0043202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Plasma lipoprotein clearance	1
Transport of small molecules	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
inflammatory response	2
ATP metabolic process	2
vesicle-mediated transport	2
hydrolase activity, acting on ester bonds	2
cell cycle	1
mitotic nuclear division	1
anatomical structure morphogenesis	1
epithelial cell proliferation	1
response to nutrient levels	1
energy homeostasis	1
hemopoiesis	1
cell differentiation	1
production of molecular mediator involved in inflammatory response	1
respiratory burst involved in defense response	1
hexose metabolic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
nicotinamide nucleotide metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
acylglycerol metabolic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
retinoid metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1

Protein interactions and networks

STRING

1848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIPA	SCGB1D2	O95969	960
LIPA	PNLIP	P16233	906
LIPA	ABCA1	O95477	730
LIPA	LIPC	P11150	711
LIPA	ADCY10	Q96PN6	674
LIPA	NPC1	O15118	657
LIPA	NPC2	P61916	646
LIPA	LIPE	Q05469	594
LIPA	PNPLA2	Q96AD5	592
LIPA	NCEH1	Q6PIU2	541
LIPA	TFEB	P19484	528
LIPA	ABCG1	P45844	526
LIPA	SCARB1	Q8WTV0	509
LIPA	APOB	P04114	508
LIPA	LDLRAP1	Q5SW96	501

IntAct

18 interactions, top by confidence:

A	B	Type	Score
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
PPM1B	RPSA2	psi-mi:“MI:0914”(association)	0.350
TMEM154	RPSA2	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
CBLN4	AGRN	psi-mi:“MI:0914”(association)	0.350
LIPA	CLGN	psi-mi:“MI:0914”(association)	0.350
MRPL21	GTPBP6	psi-mi:“MI:0914”(association)	0.350
TCF25	BCKDHA	psi-mi:“MI:0914”(association)	0.350
TTC9C	LIPA	psi-mi:“MI:0914”(association)	0.350
BCAP31	LIPA	psi-mi:“MI:0914”(association)	0.350
HBS1L	GPX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): LIPA (Proximity Label-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), CLGN (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), GAL3ST2 (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS), LIPA (Affinity Capture-MS)

ESM2 similar proteins: A5D6U8, A6H730, J3SDX8, O16956, O35409, O61866, O75795, P04068, P04634, P07098, P07099, P07687, P08430, P0DTE5, P11515, P19224, P21529, P36510, P37891, P38571, P49614, P70627, P70691, P79381, P80035, Q28611, Q29458, Q38924, Q3U4B4, Q3YBN2, Q41005, Q4R4S5, Q5VXI9, Q5VXJ0, Q5VYY2, Q5W064, Q64194, Q64435, Q64550, Q67ZU1

Diamond homologs: J3SDX8, O16956, O46107, O46108, O61866, O74430, P04634, P07098, P34163, P38571, P78898, P80035, Q29458, Q3U4B4, Q3YBN2, Q4R4S5, Q5VXI9, Q5VXJ0, Q5VYY2, Q5W064, Q64194, Q67ZU1, Q8BM14, Q8K2A6, Q93789, Q94252, Q9CPP7, Q9Z0M5, Q07950, Q71DJ5, O60095, Q07804

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

796 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	86
Uncertain significance	242
Likely benign	275
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069094	NM_000235.4(LIPA):c.37del (p.Val13fs)	Pathogenic
1076884	NC_000010.10:g.(?91005423)(91007415_?)del	Pathogenic
1323237	NM_000235.4(LIPA):c.412G>T (p.Glu138Ter)	Pathogenic
1350454	NM_000235.4(LIPA):c.1024G>C (p.Gly342Arg)	Pathogenic
1383305	NM_000235.4(LIPA):c.771_774del (p.Leu256_Cys257insTer)	Pathogenic
1404815	NM_000235.4(LIPA):c.951T>A (p.Tyr317Ter)	Pathogenic
1417455	NM_000235.4(LIPA):c.854del (p.Pro285fs)	Pathogenic
1457231	NC_000010.10:g.(?90974565)(91007425_?)del	Pathogenic
1458797	NC_000010.10:g.(?90982258)(90988165_?)del	Pathogenic
1459690	NM_000235.4(LIPA):c.600_603dup (p.Pro202fs)	Pathogenic
1459866	NM_000235.4(LIPA):c.652C>T (p.Arg218Ter)	Pathogenic
1685926	NM_000235.4(LIPA):c.647T>A (p.Leu216Ter)	Pathogenic
1723279	NC_000010.10:g.(90986762_90987956)_(90988156_91005432)del	Pathogenic
2002860	NM_000235.4(LIPA):c.618dup (p.Ala207fs)	Pathogenic
2085713	NM_000235.4(LIPA):c.511del (p.Val171fs)	Pathogenic
208594	NM_000235.4(LIPA):c.253C>T (p.Gln85Ter)	Pathogenic
2145326	NM_000235.4(LIPA):c.984C>A (p.Tyr328Ter)	Pathogenic
2741248	NM_000235.4(LIPA):c.780_781del (p.Cys261fs)	Pathogenic
2746123	NM_000235.4(LIPA):c.78dup (p.Thr27fs)	Pathogenic
2808179	NM_000235.4(LIPA):c.964C>T (p.Gln322Ter)	Pathogenic
2836288	NM_000235.4(LIPA):c.618_627del (p.Ala207fs)	Pathogenic
2858809	NM_000235.4(LIPA):c.892del (p.Gln298fs)	Pathogenic
2865584	NM_000235.4(LIPA):c.245del (p.Val82fs)	Pathogenic
2877630	NM_000235.4(LIPA):c.293_295del (p.Asn98_Leu99delinsIle)	Pathogenic
289986	NM_000235.4(LIPA):c.398del (p.Leu132_Ser133insTer)	Pathogenic
3244811	NC_000010.10:g.(?90974585)(91007408_?)del	Pathogenic
3244812	NC_000010.10:g.(?90974585)(90974838_?)del	Pathogenic
3244813	NC_000010.10:g.(?90974585)(90988175_?)del	Pathogenic
3244814	NC_000010.10:g.(?90974585)(90975786_?)del	Pathogenic
3338830	NM_000235.4(LIPA):c.229+1G>A	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:89226913:A:G	S174P	0.996
10:89228202:G:C	F142L	0.996
10:89228202:G:T	F142L	0.996
10:89228204:A:G	F142L	0.996
10:89228265:T:A	R121S	0.995
10:89228265:T:G	R121S	0.995
10:89228266:C:G	R121T	0.995
10:89228211:G:C	F139L	0.993
10:89228211:G:T	F139L	0.993
10:89228213:A:G	F139L	0.993
10:89228282:A:G	W116R	0.993
10:89228282:A:T	W116R	0.993
10:89228345:A:G	W95R	0.993
10:89228345:A:T	W95R	0.993
10:89214995:C:G	D345H	0.991
10:89228266:C:A	R121I	0.991
10:89245711:C:G	R65P	0.991
10:89214994:T:A	D345V	0.989
10:89214994:T:G	D345A	0.989
10:89222539:G:A	S289F	0.989
10:89228271:G:C	N119K	0.988
10:89228271:G:T	N119K	0.988
10:89222519:A:G	W296R	0.987
10:89222519:A:T	W296R	0.987
10:89228259:A:C	N123K	0.987
10:89228259:A:T	N123K	0.987
10:89225134:G:C	S211R	0.986
10:89225134:G:T	S211R	0.986
10:89225136:T:G	S211R	0.986
10:89226912:G:T	S174Y	0.986

dbSNP variants (sampled 300 via entrez): RS1000090444 (10:89251372 A>G), RS1000236237 (10:89242249 T>C), RS1000286828 (10:89241920 G>C), RS1000317057 (10:89223524 C>T), RS1000396005 (10:89221199 T>C), RS1000475452 (10:89248107 C>A,T), RS1000576525 (10:89225418 T>C), RS1000652245 (10:89219120 C>A,T), RS1000654288 (10:89227140 C>G,T), RS1000847430 (10:89248740 A>G), RS1001251346 (10:89217651 A>G), RS1001357145 (10:89224165 C>A,G,T), RS1001411831 (10:89230488 G>A,C), RS1001515672 (10:89237304 T>G), RS1001616245 (10:89236098 G>A)

Disease associations

OMIM: gene MIM:613497 | disease phenotypes: MIM:620151, MIM:278000

GenCC curated gene-disease

Disease	Classification	Inheritance
lysosomal acid lipase deficiency	Definitive	Autosomal recessive
Wolman disease	Supportive	Autosomal recessive
cholesteryl ester storage disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lysosomal acid lipase deficiency	Definitive	AR

Mondo (4): Wolman disease (MONDO:0019148), lysosomal acid lipase deficiency (MONDO:0800449), cholesteryl ester storage disease (MONDO:0019149), (MONDO:0010204)

Orphanet (3): Wolman disease (Orphanet:75233), Lysosomal acid lipase deficiency (Orphanet:275761), Cholesteryl ester storage disease (Orphanet:75234)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D015223	Wolman Disease	C16.320.565.398.641.201.500; C16.320.565.595.201.500; C16.614.947; C18.452.584.563.641.201.500; C18.452.648.398.641.201.500; C18.452.648.595.201.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4184 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

11 potent at pChembl≥5 of 11 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.17	IC50	68	nM	CHEMBL1085463
6.82	IC50	152	nM	CHEMBL1085857
6.72	IC50	189	nM	CHEMBL1082839
6.52	IC50	300	nM	CHEMBL1082838
6.37	IC50	424	nM	CHEMBL1082517
6.33	IC50	473	nM	CHEMBL1085856
6.31	IC50	492	nM	CHEMBL1082518
6.30	IC50	496	nM	CHEMBL1085855
5.00	IC50	1e+04	nM	CHEMBL417184
5.00	IC50	1e+04	nM	CHEMBL296516
5.00	IC50	1e+04	nM	CHEMBL3137812

PubChem BioAssay actives

8 with measured affinity, of 59 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4-piperidin-1-yl-1,2,5-thiadiazol-3-yl) morpholine-4-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.0680	uM
(4-piperidin-1-yl-1,2,5-thiadiazol-3-yl) piperidine-1-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.1520	uM
[4-(azepan-1-yl)-1,2,5-thiadiazol-3-yl] morpholine-4-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.1890	uM
[4-(azepan-1-yl)-1,2,5-thiadiazol-3-yl] piperidine-1-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.3000	uM
(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl) piperidine-1-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.4240	uM
(4-pyrrolidin-1-yl-1,2,5-thiadiazol-3-yl) morpholine-4-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.4730	uM
(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl) morpholine-4-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.4920	uM
(4-pyrrolidin-1-yl-1,2,5-thiadiazol-3-yl) piperidine-1-carboxylate	482622: Inhibition of human LAL after 30 mins by fluorescence assay	ic50	0.4960	uM

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	11
bisphenol A	affects expression, decreases methylation, increases expression	3
Nickel	affects expression, increases expression, decreases reaction	3
deoxynivalenol	decreases expression	2
trichostatin A	affects expression, decreases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Cadmium Chloride	decreases expression, increases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
linalool	increases expression	1
nickel chloride	decreases expression	1
chloroquine diphosphate	decreases expression	1
cupric chloride	decreases expression	1
nivalenol	decreases expression	1
yessotoxin	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, affects reaction	1
chloropicrin	decreases expression	1
U 0126	affects expression, affects reaction	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1119694	Binding	Inhibition of human LAL after 30 mins by fluorescence assay	Thiadiazole carbamates: potent inhibitors of lysosomal acid lipase and potential Niemann-Pick type C disease therapeutics. — J Med Chem

Cellosaurus cell lines

13 cell lines: 8 finite cell line, 2 cancer cell line, 2 induced pluripotent stem cell, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_7303	GM00863	Finite cell line	Female
CVCL_7373	GM03111	Finite cell line	Male
CVCL_8B10	GM03557	Finite cell line	Female
CVCL_8B11	GM03558	Finite cell line	Male
CVCL_D5EZ	HeLa::TMEM192-3xHA LIPA KO	Cancer cell line	Female
CVCL_E1C5	Ubigene SH-SY5Y LIPA KO	Cancer cell line	Female
CVCL_F0PZ	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) LIPA-/-	Embryonic stem cell	Female
CVCL_UD78	HT144A	Induced pluripotent stem cell	Male
CVCL_UD79	HT144B	Induced pluripotent stem cell	Male
CVCL_W621	GM02109	Finite cell line	Male

Clinical trials (associated diseases)

33 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01757184	PHASE3	COMPLETED	Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT01488097	PHASE2	COMPLETED	Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of SBC-102 (Sebelipase Alfa) in Adult Subjects With Lysosomal Acid Lipase Deficiency
NCT02112994	PHASE2	COMPLETED	Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
NCT02193867	PHASE2	TERMINATED	Clinical Study In Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT04532047	PHASE1	RECRUITING	PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT01371825	PHASE2/PHASE3	COMPLETED	Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
NCT01307098	PHASE1/PHASE2	COMPLETED	Safety, Tolerability and Pharmacokinetics of SBC-102 (Sebelipase Alfa) in Adult Participants With Lysosomal Acid Lipase Deficiency
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT01358370	Not specified	COMPLETED	A Retrospective Natural History Study of Patients With Lysosomal Acid Lipase Deficiency/Wolman Phenotype
NCT01528917	Not specified	COMPLETED	An Observational Study of Patients With Lysosomal Acid Lipase Deficiency/Cholesteryl Ester Storage Disease Phenotype
NCT01633489	Not specified	RECRUITING	Lysosomal Acid Lipase (LAL) Deficiency Registry
NCT01716728	Not specified	UNKNOWN	Identification of Undiagnosed Lysosomal Acid Lipase Deficiency
NCT01884220	Not specified	COMPLETED	Wolman/CESD Natural History Chart Review and Longitudinal Follow-Up
NCT02345421	Not specified	TERMINATED	A Study to Identify and Characterize LAL-D Patients in High-risk Populations
NCT02376751	Not specified	NO_LONGER_AVAILABLE	An Expanded Access Protocol for Sebelipase Alfa for Patients With Lysosomal Acid Lipase Deficiency
NCT02926872	Not specified	TERMINATED	Screening for Lysosomal Acid Lipase Deficiency
NCT03564002	Not specified	UNKNOWN	Metabolic Effects of Very Low Carbohydrate Ketogenic Diet in Subjects With Severe Obesity
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03984149	Not specified	UNKNOWN	Lipa Gene Mutation in PED-LIPIGEN (Pediatric FH Subjects)
NCT04652713	Not specified	COMPLETED	Breakfast for Young Women
NCT04792671	Not specified	UNKNOWN	Prevalence and Risk Factors of Women Mental Health Disorders
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT05619900	Not specified	RECRUITING	Registry of Patients Diagnosed With Lysosomal Storage Diseases
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06287658	Not specified	UNKNOWN	The Effect of Kegel Exercise and Ba Duan Jin Applications on Premenopausal Women With Urinary Incontinence
NCT07455864	Not specified	RECRUITING	Lysosomal Acid Lipase Deficiency in Risk Groups
NCT01791452	Not specified	UNKNOWN	Novel Association of Cholesterol Ester Storage Disease Due to Lysosomal Acid Lipase Deficiency and Non-Alcoholic Fatty Liver Disease: A Prospective Clinical Study
NCT02372513	Not specified	COMPLETED	National Lysosomal Acid Lipase Deficiency Study
NCT02383641	Not specified	WITHDRAWN	Biomarker for Wolman Disease (BioWolman)