LIPE

Summary

LIPE (lipase E, hormone sensitive type, HGNC:6621) is a protein-coding gene on chromosome 19q13.2, encoding Hormone-sensitive lipase (Q05469). Lipase with broad substrate specificity, catalyzing the hydrolysis of triacylglycerols (TAGs), diacylglycerols (DAGs), monoacylglycerols (MAGs), cholesteryl esters and retinyl esters.

The protein encoded by this gene has a long and a short form, generated by use of alternative translational start codons. The long form is expressed in steroidogenic tissues such as testis, where it converts cholesteryl esters to free cholesterol for steroid hormone production. The short form is expressed in adipose tissue, among others, where it hydrolyzes stored triglycerides to free fatty acids.

Source: NCBI Gene 3991 — RefSeq curated summary.

At a glance

• Gene–disease (curated): LIPE-related familial partial lipodystrophy (Definitive, ClinGen)
• Clinical variants (ClinVar): 268 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes
• MANE Select transcript: NM_005357

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6621
Approved symbol	LIPE
Name	lipase E, hormone sensitive type
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	HSL
Ensembl gene	ENSG00000079435
Ensembl biotype	protein_coding
OMIM	151750
Entrez	3991

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000244289, ENST00000597001, ENST00000597620, ENST00000599211, ENST00000599783, ENST00000599918, ENST00000600224, ENST00000601189, ENST00000602000

RefSeq mRNA: 10 — MANE Select: NM_005357 NM_001416100, NM_001416101, NM_001416102, NM_001416103, NM_001416104, NM_001416105, NM_001416106, NM_001416107, NM_001416108, NM_005357

CCDS: CCDS12607

Canonical transcript exons

ENST00000244289 — 10 exons

Exon	Start	End
ENSE00000709257	42406161	42406388
ENSE00000709260	42405385	42405561
ENSE00000709262	42402607	42403031
ENSE00001162583	42426267	42427388
ENSE00001194800	42401514	42402075
ENSE00003076590	42407174	42407468
ENSE00004034694	42407976	42408121
ENSE00004034696	42407606	42407791
ENSE00004034697	42408232	42408322
ENSE00004034698	42410307	42410842

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1310 / max 2297.0978, expressed in 923 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181186	11.8181	226
181190	1.4375	689
181189	0.6774	317
181187	0.0950	36
181191	0.0685	14
181192	0.0302	9
181188	0.0043	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
omental fat pad	UBERON:0010414	98.67	gold quality
peritoneum	UBERON:0002358	98.63	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.87	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.79	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.63	gold quality
adipose tissue	UBERON:0001013	97.34	gold quality
spinal cord	UBERON:0002240	96.34	gold quality
connective tissue	UBERON:0002384	95.56	gold quality
pericardium	UBERON:0002407	94.94	gold quality
right testis	UBERON:0004534	94.68	gold quality
left testis	UBERON:0004533	94.59	gold quality
inferior vagus X ganglion	UBERON:0005363	93.58	silver quality
apex of heart	UBERON:0002098	93.09	gold quality
middle frontal gyrus	UBERON:0002702	93.00	gold quality
inferior olivary complex	UBERON:0002127	92.49	silver quality
olfactory bulb	UBERON:0002264	92.04	gold quality
subthalamic nucleus	UBERON:0001906	91.89	silver quality
right adrenal gland cortex	UBERON:0035827	91.40	gold quality
type B pancreatic cell	CL:0000169	91.05	gold quality
right adrenal gland	UBERON:0001233	90.99	gold quality
left adrenal gland cortex	UBERON:0035825	90.76	gold quality
left adrenal gland	UBERON:0001234	90.57	gold quality
adrenal cortex	UBERON:0001235	90.53	gold quality
testis	UBERON:0000473	90.49	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	90.36	silver quality
substantia nigra	UBERON:0002038	90.33	gold quality
midbrain	UBERON:0001891	90.28	gold quality
corpus callosum	UBERON:0002336	89.79	gold quality
heart left ventricle	UBERON:0002084	89.59	gold quality
adrenal gland	UBERON:0002369	89.52	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, DGKQ, ID2, NFKB1, NR1H3, NR5A1, PPARG, RELA, RXRA, SP1, SREBF1, TCF3, USF1

miRNA regulators (miRDB)

11 targeting LIPE, 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-6867-5P	100.00	82.21	3464
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-3714	99.71	70.74	2671

Literature-anchored findings (GeneRIF, showing 40)

• genes of C3, hormone-sensitive lipase, and PPARgamma may exert a modifying effect on lipid and glucose metabolism in familial combined hypersensitivity (PMID:11979403)
• overexpression of HSL, despite increased lipase activity, does not lead to enhanced lipolysis (PMID:12518034)
• HSL i6 A5 HOMOZYGOSITY IS A RISK FACTOR FOR BODY FAT ACCUMULATION (PMID:12534454)
• high concentrations of estradiol significantly increased both hormone-sensitive lipase expression and glycerol release relative to control (PMID:12701046)
• lipolytic catecholamine resistance of sc adipocytes in polycystic ovary syndrome is probably due to a combination of decreased amounts of beta(2)-adrenergic receptors, the regulatory II beta-component of protein kinase A, and hormone-sensitive lipase (PMID:12727985)
• High adrenaline levels can stimulate hormone-sensitive lipase(HSL) activity regardless of metabolic milieu. Large increases in adrenaline during exercise are able to further stimulate contraction-induced increase in HSL activity. (PMID:12730334)
• The presence of a catalytically inactive variant of this enzyme is associated with decreased lipolysis in abdominal subcutaneous adipose tissue of obese subjects (PMID:12765952)
• role of cyclic GMP in natriuretic peptide-mediated phosphorylation in adipocytes (PMID:12970365)
• AMPK is a major regulator of skeletal muscle HSL activity that can override beta-adrenergic stimulation (PMID:15231718)
• catalytic serine of hormone-sensitive lipase is highly reactive and similar behavior was also observed with lipases with no lid domain covering their active site, or with a deletion in the lid domain (PMID:15260473)
• 5’AMP-activated protein kinase phosphorylates hormone-sensitive lipase on Ser565 in human skeletal muscle during exercise with reduced muscle glycogen. Apparently, HSL Ser565 phosphorylation by AMPK during exercise (PMID:15308678)
• mechanism of infertility in HSL-deficient males is cell autonomous and resides in postmeiotic germ cells, because HSL expression in these cells is in itself sufficient to restore normal fertility (PMID:15345679)
• a pre-lipolysis complex containing at least AFABP and HSL exists (PMID:15456755)
• Basal HSL is decreased in patients with type 2 diabetes mellitus, and this may be a consequence of elevated plasma insulin levels. (PMID:15609025)
• Perilipin targets a novel pool of lipid droplets for lipolytic attack by hormone-sensitive lipase (PMID:16243839)
• the HSL C-60G polymorphism is associated with increased waist circumference in non-obese subjects (PMID:16534522)
• adrenergic stimulation contributes to the increase in HSL activity that occurs in human skeletal muscle in the first minute of exercise at 65% and 90% VO2 peak (PMID:16690773)
• HSL gene expression shows a regulation according to obesity status and is associated with increased adipose tissue lipase activity. (PMID:16752181)
• although HSL expression and Ser(659) phosphorylation in skeletal muscle during exercise is sex specific, total muscle HSL activity measured in vitro was similar between sexes (PMID:16822962)
• maternal type 1 diabetes is associated with TG accumulation and increased EL and HSL gene expression in placenta (PMID:16940551)
• hormone-sensitive lipase (PMID:17026959)
• Adipose triglyceride lipase and hormone sensitive lipase are responsible for more than 95% of the triacylglycerol hydrolase activity present in murine white adipose tissue. (PMID:17074755)
• The combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of gestational hypertension, but seemingly not of preeclampsia. (PMID:17318300)
• Adipose triglyceride lipase (ATGL) is less important than hormone-sensitive lipase (HSL) in regulating catecholamine-induced lipolysis. Both lipases regulate basal lipolysis in human adipocytes. ATGL expression is not influenced by obesity or PCOS. (PMID:17327373)
• In obese subjects, insulin resistance and hyperinsulinemia are strongly associated with ATGL and HSL mRNA and protein expression, independent of fat mass (PMID:17356053)
• Dydrogesterone and norethisterone increase secretion of HSL from abdominaal adipocytes. (PMID:17587400)
• variation of the HSL gene might be associated with a physiological effect on in vivo beta-adrenoceptor-mediated fat oxidation (PMID:18249203)
• Real-time PCR revealed that large adipocytes expressed higher mRNA levels of hormone sensitive lipase. (PMID:18383440)
• Obesity is accompanied by impaired fasting glycerol release, lower HSL protein expression, and serine phosphorylation. (PMID:18398140)
• Mapping of the hormone-sensitive lipase binding site on the adipocyte fatty acid-binding protein (AFABP). Identification of the charge quartet on the AFABP/aP2 helix-turn-helix domain. (PMID:18820256)
• analysis of human, mouse and ovine Hormone Sensitive Lipase (PMID:18824087)
• PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650 (PMID:19018281)
• These results suggest that the associations between physical activity and body fat and plasma lipoprotein/lipid concentrations in men are dependent on the LIPE C-60G polymorphism,. (PMID:19164092)
• results suggest that ATGL/CGI-58 acts independently of HSL and precedes its action in the sequential hydrolysis of triglycerides in human hMADS adipocytes (PMID:19433586)
• TNFalpha decreased ATGL and HSL protein content and triglycerides (TG)-hydrolase activity but increased basal lipolysis due to a marked reduction in perilipin (PLIN) protein content (PMID:19695247)
• The present study aimed at comparing expression and subcellular distribution of perilipin and hormone-sensitive lipase in two abdominal adipose tissues of lean and obese women. (PMID:20017959)
• Those findings indicate improvement and conservation of lifestyle depending on genetic predisposition in ADIPOQ, PLIN and LIPE should be encouraged. (PMID:20495294)
• Data show that hormone-sensitive lipase activity is reduced in adipose tissue of patients with and without diabetes, while lipoprotein lipase activity is reduces only in patients with diabetes. (PMID:20926921)
• It is concluded that ACTH via the PKA pathway stimulates expression of SF-1, which activates transcription of LIPE presumably by interaction with putative binding sequences within promoter A (PMID:21081692)
• Studies indicate tha HSL is regulated by reversible phosphorylation on five critical residues. (PMID:21241784)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	lipea	ENSDARG00000063037
danio_rerio	lipeb	ENSDARG00000101145
mus_musculus	Lipe	ENSMUSG00000003123
rattus_norvegicus	Lipe	ENSRNOG00000020546
drosophila_melanogaster	Hsl	FBGN0034491
caenorhabditis_elegans		WBGENE00016704

Protein

Protein identifiers

Hormone-sensitive lipase — Q05469 (reviewed: Q05469)

Alternative names: Monoacylglycerol lipase LIPE, Retinyl ester hydrolase

All UniProt accessions (7): Q05469, M0QXB1, M0QXM5, M0QY29, M0QYP8, M0R201, M0R2G1

UniProt curated annotations — full annotation on UniProt →

Function. Lipase with broad substrate specificity, catalyzing the hydrolysis of triacylglycerols (TAGs), diacylglycerols (DAGs), monoacylglycerols (MAGs), cholesteryl esters and retinyl esters. Shows a preferential hydrolysis of DAGs over TAGs and MAGs and preferentially hydrolyzes the fatty acid (FA) esters at the sn-3 position of the glycerol backbone in DAGs. Preferentially hydrolyzes FA esters at the sn-1 and sn-2 positions of the glycerol backbone in TAGs. Catalyzes the hydrolysis of 2-arachidonoylglycerol, an endocannabinoid and of 2-acetyl monoalkylglycerol ether, the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor. In adipose tissue and heart, it primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production.

Subunit / interactions. Monomer and homodimer. Interacts with CAVIN1 in the adipocyte cytoplasm. Interacts with PLIN5.

Subcellular location. Cell membrane. Membrane. Caveola. Cytoplasm. Cytosol. Lipid droplet.

Tissue specificity. Testis.

Post-translational modifications. Phosphorylation by AMPK reduces its translocation towards the lipid droplets.

Disease relevance. Lipodystrophy, familial partial, 6 (FPLD6) [MIM:615980] An autosomal recessive form of lipodystrophy characterized by abnormal subcutaneous fat distribution. Affected individuals have increased visceral fat, impaired lipolysis, dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. Some patients manifest muscular dystrophy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Retinyl ester hydrolase is inhibited by bis-p-nitrophenyl phosphate.

Pathway. Glycerolipid metabolism; triacylglycerol degradation.

Similarity. Belongs to the ‘GDXG’ lipolytic enzyme family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q05469-1	1, Testicular	yes
Q05469-2	2

RefSeq proteins (10): NP_001403029, NP_001403030, NP_001403031, NP_001403032, NP_001403033, NP_001403034, NP_001403035, NP_001403036, NP_001403037, NP_005348* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002168	Lipase_GDXG_HIS_AS	Active_site
IPR010468	HSL_N	Domain
IPR013094	AB_hydrolase_3	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR033140	Lipase_GDXG_put_SER_AS	Active_site

Pfam: PF06350, PF07859

Enzyme classification (BRENDA):

• EC 3.1.1.79 — hormone-sensitive lipase (BRENDA: 22 organisms, 222 substrates, 108 inhibitors, 149 Km, 116 kcat entries)

Substrate kinetics (BRENDA)

64 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FLUORESCEIN DIACETOXYMETHYL ETHER	0.0002–0.082	18
FLUORESCEIN DI(METHOXY)ACETOXYMETHYL ETHER	0.0011–0.694	17
FLUORESCEIN BIS((5-OXAZOLYL)CARBOXYMETHYL ETHER)	—	15
CHOLESTERYL OLEATE	0.0022–0.099	9
4-NITROPHENYL ACETATE	0.28–7.42	7
4-NITROPHENYL BUTYRATE	0.02–1.97	5
4-NITROPHENYL OLEATE	0.268–0.462	4
P-NITROPHENYL ACETATE	0.28–7.42	4
2-NAPHTHYL ACETATE	0.0077–5.43	2
4-NITROPHENYL HEXANOATE	1.4–2.32	2
4-NITROPHENYL PALMITATE	0.363–0.376	2
P-NITROPHENYL BUTYRATE	0.164–1.06	2
P-NITROPHENYL HEXANOATE	0.03–0.054	2
VINYL ACETATE	170–315	2
VINYL BUTYRATE	10–25	2

Catalyzed reactions (Rhea), 12 shown:

• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• all-trans-retinyl hexadecanoate + H2O = all-trans-retinol + hexadecanoate + H(+) (RHEA:13933)
• a monoacylglycerol + H2O = glycerol + a fatty acid + H(+) (RHEA:15245)
• 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H2O = glycerol + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:26132)
• a diacylglycerol + H2O = a monoacylglycerol + a fatty acid + H(+) (RHEA:32731)
• cholesteryl (9Z-octadecenoate) + H2O = cholesterol + (9Z)-octadecenoate + H(+) (RHEA:33875)
• 1,2-di-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O (RHEA:38379)
• 2,3-di-(9Z)-octadecenoyl-sn-glycerol + H2O = 2-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:38383)
• 1,2-di-(9Z-octadecenoyl)-glycerol + H2O = (9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:38455)
• 1-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38487)
• 2-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38491)
• 1-O-hexadecyl-2-acetyl-sn-glycerol + H2O = 1-O-hexadecyl-sn-glycerol + acetate + H(+) (RHEA:38563)

UniProt features (39 total): compositionally biased region 10, sequence variant 10, modified residue 6, region of interest 4, active site 3, sequence conflict 3, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8ZVQ	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05469-F1	64.77	0.37

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 (3): 725; 994; 1024

Post-translational modifications (6): 853, 855, 897, 929, 950, 951

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-163560	Triglyceride catabolism
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1430728	Metabolism
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-556833	Metabolism of lipids
R-HSA-74160	Gene expression (Transcription)
R-HSA-8979227	Triglyceride metabolism
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 249 (showing top): REACTOME_TRIGLYCERIDE_CATABOLISM, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, GOBP_NEUTRAL_LIPID_CATABOLIC_PROCESS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_6, GOBP_LIPID_METABOLIC_PROCESS, GOBP_TRIGLYCERIDE_CATABOLIC_PROCESS, MAGRANGEAS_MULTIPLE_MYELOMA_IGG_VS_IGA_UP, GOBP_NEUTRAL_LIPID_METABOLIC_PROCESS, NAKAYAMA_SOFT_TISSUE_TUMORS_PCA2_DN, GOBP_DIACYLGLYCEROL_METABOLIC_PROCESS, GOBP_GLYCEROLIPID_CATABOLIC_PROCESS

GO Biological Process (9): protein phosphorylation (GO:0006468), cholesterol metabolic process (GO:0008203), lipid catabolic process (GO:0016042), triglyceride catabolic process (GO:0019433), diacylglycerol catabolic process (GO:0046340), ether lipid metabolic process (GO:0046485), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), retinol metabolic process (GO:0042572)

GO Molecular Function (9): sterol ester esterase activity (GO:0004771), triacylglycerol lipase activity (GO:0004806), monoacylglycerol lipase activity (GO:0047372), all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity (GO:0047376), retinyl-palmitate esterase activity (GO:0050253), diacylglycerol lipase activity (GO:0120516), protein binding (GO:0005515), lipase activity (GO:0016298), hydrolase activity (GO:0016787)

GO Cellular Component (6): lipid droplet (GO:0005811), cytosol (GO:0005829), caveola (GO:0005901), membrane (GO:0016020), cytoplasm (GO:0005737), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Triglyceride metabolism	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Gene expression (Transcription)	1
Metabolism	1
Metabolism of lipids	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipase activity	4
carboxylic ester hydrolase activity	4
lipid metabolic process	3
cellular anatomical structure	3
acylglycerol catabolic process	2
phosphorylation	1
protein modification process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
catabolic process	1
triglyceride metabolic process	1
diacylglycerol metabolic process	1
primary metabolic process	1
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
retinyl-palmitate esterase activity	1
retinol metabolic process	1
binding	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
intracellular membraneless organelle	1
cytoplasm	1
plasma membrane raft	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIPE	PLIN1	O60240	996
LIPE	FABP4	P15090	994
LIPE	PNPLA2	Q96AD5	968
LIPE	MGLL	Q99685	925
LIPE	ABHD5	Q8WTS1	914
LIPE	LPL	P06858	899
LIPE	PRKACA	P17612	899
LIPE	PRKACG	P22612	899
LIPE	PRKACB	P22694	898
LIPE	MLXIPL	Q9NP71	892
LIPE	PNPLA3	Q9NST1	870
LIPE	PPARG	P37231	842
LIPE	ADRB3	P13945	826
LIPE	PLIN2	Q99541	825
LIPE	ADIPOQ	Q15848	822

IntAct

8 interactions, top by confidence:

A	B	Type	Score
LIPE	TSGA10IP	psi-mi:“MI:0915”(physical association)	0.560
ORF36	PTCD1	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
LIPE	MTNR1A	psi-mi:“MI:0915”(physical association)	0.000
TSGA10IP	LIPE	psi-mi:“MI:0915”(physical association)	0.000
NSFL1C	LIPE	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): PLIN1 (FRET), PLIN1 (PCA), LIPE (FRET), FABP4 (FRET), PLIN1 (FRET), PLIN5 (FRET), PLIN2 (FRET), PLIN1 (Affinity Capture-Western), PLIN5 (Affinity Capture-Western), PLIN2 (Affinity Capture-Western), PLIN3 (Affinity Capture-Western), LIPE (Two-hybrid), LIPE (Two-hybrid), TSGA10IP (Two-hybrid), LIPE (Affinity Capture-MS)

ESM2 similar proteins: A1A5Q6, A6NF34, A6NNT2, B0BF33, D3ZF92, O43278, O75509, O88393, P08920, P08921, P25236, P26342, P35054, P49907, P49908, P51843, P70274, P70503, P79386, Q03167, Q05469, Q13342, Q1LVK9, Q4JF29, Q4R7B7, Q5F378, Q5QGU6, Q5R8W9, Q61066, Q6AY06, Q6P7C7, Q6S545, Q8BHP7, Q8BVM2, Q8VHF2, Q91ZV2, Q921T2, Q96PD2, Q99P91, Q99PS8

Diamond homologs: A0A0A1EQ07, A0A0H5BMX5, A0A2P1GIW2, A0A2P1GIW3, A0A2P1GIY1, A0A2P1GIY2, B5BLW5, I3PLR2, I4DST8, I4DST9, O06350, O53424, O64640, O64641, P15304, P16386, P22760, P24484, P37967, P54310, P9WK86, P9WK87, Q00675, Q05469, Q0CZH0, Q0P5B7, Q0ZPV7, Q5NUF3, Q5NUF4, Q5R8Y5, Q68J42, Q6PIU2, Q7D5F9, Q7M370, Q940G6, Q9EX73, Q9FG13, Q9FX92, Q9FX93, Q9FX94

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
AMPK	down-regulates	LIPE	phosphorylation
CAMK2A	down-regulates	LIPE	phosphorylation
PRKAA1	down-regulates	LIPE	phosphorylation
PRKACA	down-regulates	LIPE	phosphorylation
PRKACA	“up-regulates activity”	LIPE	phosphorylation
MAPK1	“up-regulates activity”	LIPE	phosphorylation
MAPK3	“up-regulates activity”	LIPE	phosphorylation
Gbeta	“up-regulates activity”	LIPE	phosphorylation
ERK1/2	“up-regulates activity”	LIPE	phosphorylation
PKA	“up-regulates activity”	LIPE	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	179
Likely benign	36
Benign	36

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
180647	NM_005357.4(LIPE):c.1519_1520dup (p.Ser508fs)	Pathogenic
4682129	NM_005357.4(LIPE):c.1111_1120dup (p.Arg374fs)	Pathogenic
1028370	NM_005357.4(LIPE):c.2152C>T (p.Arg718Ter)	Likely pathogenic
4845693	NM_005357.4(LIPE):c.232C>T (p.Gln78Ter)	Likely pathogenic

SpliceAI

1771 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42402072:ACGC:A	acceptor_gain	1.0000
19:42402072:ACGCC:A	acceptor_loss	1.0000
19:42402073:CGC:C	acceptor_gain	1.0000
19:42402073:CGCC:C	acceptor_gain	1.0000
19:42402076:C:A	acceptor_loss	1.0000
19:42402077:T:A	acceptor_loss	1.0000
19:42405382:CACCT:C	donor_loss	1.0000
19:42405383:A:AC	donor_gain	1.0000
19:42405383:AC:A	donor_gain	1.0000
19:42405383:ACCTG:A	donor_gain	1.0000
19:42405384:C:CA	donor_gain	1.0000
19:42405384:CC:C	donor_gain	1.0000
19:42405384:CCT:C	donor_gain	1.0000
19:42405384:CCTG:C	donor_gain	1.0000
19:42405384:CCTGC:C	donor_gain	1.0000
19:42405561:CCTG:C	acceptor_loss	1.0000
19:42405562:C:CC	acceptor_gain	1.0000
19:42405562:CTGC:C	acceptor_loss	1.0000
19:42405565:C:CT	acceptor_gain	1.0000
19:42407168:GCTCA:G	donor_loss	1.0000
19:42407169:CTCA:C	donor_loss	1.0000
19:42407170:TCA:T	donor_loss	1.0000
19:42407171:CA:C	donor_loss	1.0000
19:42407172:A:AC	donor_gain	1.0000
19:42407172:A:AT	donor_loss	1.0000
19:42407173:C:CC	donor_gain	1.0000
19:42407464:CTGTC:C	acceptor_gain	1.0000
19:42407467:TC:T	acceptor_gain	1.0000
19:42407468:CC:C	acceptor_gain	1.0000
19:42407469:C:CC	acceptor_gain	1.0000

AlphaMissense

6875 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42401965:G:C	F1026L	0.999
19:42401965:G:T	F1026L	0.999
19:42401967:A:G	F1026L	0.999
19:42407303:A:G	W670R	0.999
19:42407303:A:T	W670R	0.999
19:42407346:A:C	F655L	0.999
19:42407346:A:T	F655L	0.999
19:42407348:A:G	F655L	0.999
19:42406344:C:A	G728W	0.998
19:42406351:A:C	S725R	0.998
19:42406351:A:T	S725R	0.998
19:42406353:T:G	S725R	0.998
19:42406355:T:A	D724V	0.998
19:42406359:C:A	G723W	0.998
19:42407217:G:C	C698W	0.998
19:42407356:C:A	G652V	0.998
19:42407360:G:C	H651D	0.998
19:42401966:A:G	F1026S	0.997
19:42406337:A:G	L730P	0.997
19:42406346:C:A	G727V	0.997
19:42406346:C:T	G727D	0.997
19:42406352:C:A	S725I	0.997
19:42406355:T:G	D724A	0.997
19:42406358:C:T	G723E	0.997
19:42408005:A:G	W543R	0.997
19:42408005:A:T	W543R	0.997
19:42401973:G:C	H1024D	0.996
19:42406333:G:C	C731W	0.996
19:42406343:C:T	G728E	0.996
19:42406355:T:C	D724G	0.996

dbSNP variants (sampled 300 via entrez): RS1000020124 (19:42428236 T>C), RS1000082000 (19:42417757 A>G), RS1000256612 (19:42422547 G>A), RS1000369370 (19:42401682 T>C,G), RS1000397774 (19:42406419 C>A,T), RS1000472766 (19:42411988 A>G), RS1000818613 (19:42427333 G>A,C), RS1000872620 (19:42404685 C>T), RS1000963502 (19:42411020 C>T), RS1001079272 (19:42410468 T>C,G), RS1001082562 (19:42416463 G>A), RS1001136925 (19:42416797 C>T), RS1001178496 (19:42418643 G>A), RS1001343466 (19:42410673 G>T), RS1001494634 (19:42428313 C>T)

Disease associations

OMIM: gene MIM:151750 | disease phenotypes: MIM:615980

GenCC curated gene-disease

Disease	Classification	Inheritance
LIPE-related familial partial lipodystrophy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
LIPE-related familial partial lipodystrophy	Definitive	AR

Mondo (1): LIPE-related familial partial lipodystrophy (MONDO:0014431)

Orphanet (1): LIPE-related familial partial lipodystrophy (Orphanet:435660)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000147	Polycystic ovaries
HP:0000468	Increased adipose tissue around the neck
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000876	Oligomenorrhea
HP:0000956	Acanthosis nigricans
HP:0001010	Hypopigmentation of the skin
HP:0001324	Muscle weakness
HP:0001397	Hepatic steatosis
HP:0001761	Pes cavus
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002938	Lumbar hyperlordosis
HP:0003077	Hyperlipidemia
HP:0003119	Abnormal circulating lipid concentration
HP:0003198	Myopathy
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003292	Decreased serum leptin
HP:0003551	Difficulty climbing stairs
HP:0003560	Muscular dystrophy
HP:0003635	Loss of subcutaneous adipose tissue in limbs
HP:0003701	Proximal muscle weakness
HP:0003712	Skeletal muscle hypertrophy
HP:0007340	Lower limb muscle weakness
HP:0008993	Increased intraabdominal fat
HP:0008994	Proximal lower limb muscle weakness

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3590 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Hydrolases & Lipases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 41 [PMID: 15026062]	Inhibition	9.0	pIC50

Binding affinities (BindingDB)

100 measured of 119 human assays (119 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(5S,7S,8R)-8-hydroxy-7-propan-2-yl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	2.4 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(5S,7R,8R)-8-hydroxy-7-propyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	3.7 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-[4-(trifluoromethyl)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	7.7 nM	US-8703807: Azaspirodecanone compounds
8-(2-fluoroethoxymethyl)-8-hydroxy-2-[6-[(2S)-1,1,1-trifluoropropan-2-yl]oxy-3-pyridinyl]-2-azaspiro[4.5]decan-1-one	IC50	10 nM	US-8703807: Azaspirodecanone compounds
8-hydroxy-2-(6-propan-2-yloxy-3-pyridinyl)-8-(2,2,2-trifluoroethoxymethyl)-2-azaspiro[4.5]decan-1-one	IC50	13.7 nM	US-8703807: Azaspirodecanone compounds
(5S,7S,8R)-8-hydroxy-7-propan-2-yl-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	16.2 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
8-(2,2-difluoroethoxymethyl)-8-hydroxy-2-(4-propan-2-yloxyphenyl)-2-azaspiro[4.5]decan-1-one	IC50	16.3 nM	US-8703807: Azaspirodecanone compounds
8-hydroxy-8-[(2-oxopiperidin-1-yl)methyl]-2-(4-propan-2-yloxyphenyl)-2-azaspiro[4.5]decan-1-one	IC50	27.4 nM	US-8703807: Azaspirodecanone compounds
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-[4-[(2R)-1,1,1-trifluoropropan-2-yl]oxyphenyl]-2-azaspiro[4.5]decan-1-one	IC50	30.6 nM	US-8703807: Azaspirodecanone compounds
(3aR,7aS)-2-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	33 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
8-(2-fluoroethoxymethyl)-8-hydroxy-2-(4-propan-2-yloxyphenyl)-2-azaspiro[4.5]decan-1-one	IC50	37 nM	US-8703807: Azaspirodecanone compounds
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-[6-[(2S)-1,1,1-trifluoropropan-2-yl]oxy-3-pyridinyl]-2-azaspiro[4.5]decan-1-one	IC50	41.8 nM	US-8703807: Azaspirodecanone compounds
(5S,7S,8S)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	42.1 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(6S,7aS)-6-hydroxy-6-(2,2,2-trifluoroethoxymethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,5,7,7a-tetrahydropyrrolo[1,2-c]imidazol-3-one	IC50	43.2 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(3aS,7aR)-2-(2-phenylacetyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	49.5 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(3aS,7aR)-2-(2-chlorophenyl)sulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	50.1 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-(4-propan-2-yloxyphenyl)-2-azaspiro[4.5]decan-1-one	IC50	50.9 nM	US-8703807: Azaspirodecanone compounds
(3aR,7aS)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethoxy)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	51.2 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(5S,7R,8R)-8-hydroxy-7-propyl-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	67 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
8-hydroxy-8-[(2-oxopiperidin-1-yl)methyl]-2-[4-(trifluoromethyl)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	68.1 nM	US-8703807: Azaspirodecanone compounds
(5R,7R,8R)-8-hydroxy-7-propoxy-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	73.3 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
N-[(3aS,6aR)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-2-chlorobenzenesulfonamide	IC50	96.5 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
N-[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-chlorobenzenesulfonamide	IC50	132 nM	US-8497288: Hexahydropyrroloimidazolone compounds
N-[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-fluorobenzenesulfonamide	IC50	135 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(5R,7R,8R)-8-hydroxy-7-propan-2-yloxy-2-[4-[(1R)-2,2,2-trifluoro-1-methoxyethyl]phenyl]-2-azaspiro[4.5]decan-1-one	IC50	136 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(3aS,7aR)-4-oxo-N,5-bis[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxamide	IC50	136 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(3aS,5S,6aR)-5-(butoxymethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-3-one	IC50	139 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
2-[(3aR,7aS)-4-oxo-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-2-yl]-N-(4-fluorophenyl)-3-methylbutanamide	IC50	153 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	158 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(3aR,7aS)-2-(2-chlorophenyl)sulfonyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	161 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
N-[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-4-chlorobenzamide	IC50	169 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(3aS,7aR)-2-benzylsulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	174 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-[4-[(1R)-2,2,2-trifluoro-1-methoxyethyl]phenyl]-2-azaspiro[4.5]decan-1-one	IC50	175 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-[4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl]-2-azaspiro[4.5]decan-1-one	IC50	185 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(5R,7R,8R)-8-hydroxy-7-propan-2-yloxy-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	189 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
(5R,7R,8R)-7-ethoxy-8-hydroxy-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decan-1-one	IC50	198 nM	US-8722721: SEC-hydroxycyclohexyl derivatives
[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl] N-(3-fluorophenyl)-N-methylcarbamate	IC50	203 nM	US-8497288: Hexahydropyrroloimidazolone compounds
N-[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-chloropyridine-3-sulfonamide	IC50	212 nM	US-8497288: Hexahydropyrroloimidazolone compounds
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-[4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl]-2-azaspiro[4.5]decan-1-one	IC50	213 nM	US-8703807: Azaspirodecanone compounds
N-[(6S,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-fluorobenzenesulfonamide	IC50	222 nM	US-8497288: Hexahydropyrroloimidazolone compounds
N-[(6S,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-4-methylbenzenesulfonamide	IC50	233 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(3aR,7aS)-2-[2-(4-methylphenyl)acetyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	244 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(3aS,7aR)-2-(4-propan-2-ylbenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	259 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
8-hydroxy-8-[(2-oxopyrrolidin-1-yl)methyl]-2-(6-propan-2-yloxy-3-pyridinyl)-2-azaspiro[4.5]decan-1-one	IC50	264 nM	US-8703807: Azaspirodecanone compounds
(3aR,7aS)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethyl)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	268 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
(3aS,5S,6aR)-5-(anilinomethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-3-one	IC50	279 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds
N-[(6R,7aS)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-phenoxyacetamide	IC50	288 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(6S,7aS)-6-(ethoxymethyl)-6-hydroxy-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,5,7,7a-tetrahydropyrrolo[1,2-c]imidazol-3-one	IC50	298 nM	US-8497288: Hexahydropyrroloimidazolone compounds
N-[(6S,7aR)-3-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-2-chlorobenzenesulfonamide	IC50	305 nM	US-8497288: Hexahydropyrroloimidazolone compounds
(3aS,7aR)-2-(2-chlorobenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one	IC50	311 nM	US-8501768: Hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds

ChEMBL bioactivities

388 potent at pChembl≥5 of 390 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL106375
9.00	IC50	1	nM	CHEMBL419197
9.00	IC50	1	nM	CHEMBL322794
9.00	IC50	1	nM	CHEMBL49895
8.70	IC50	2	nM	CHEMBL107197
8.70	IC50	2	nM	CHEMBL110343
8.70	IC50	2	nM	CHEMBL109116
8.70	IC50	2	nM	CHEMBL4063082
8.62	IC50	2.4	nM	CHEMBL3643710
8.52	IC50	3	nM	CHEMBL107197
8.52	IC50	3	nM	CHEMBL320813
8.52	IC50	3	nM	CHEMBL295166
8.52	IC50	3	nM	CHEMBL106581
8.52	IC50	3	nM	CHEMBL106126
8.43	IC50	3.7	nM	CHEMBL3643709
8.40	IC50	4	nM	CHEMBL105834
8.40	IC50	4	nM	CHEMBL110763
8.40	IC50	4	nM	CHEMBL110343
8.40	IC50	4	nM	CHEMBL317407
8.40	IC50	4	nM	CHEMBL108523
8.40	IC50	4	nM	CHEMBL106784
8.40	IC50	4	nM	CHEMBL106756
8.30	IC50	5	nM	CHEMBL107365
8.30	IC50	5	nM	CHEMBL49417
8.30	IC50	5	nM	CHEMBL106045
8.30	IC50	5	nM	CHEMBL110653
8.30	IC50	5	nM	CHEMBL320249
8.30	IC50	5	nM	CHEMBL106314
8.22	IC50	6	nM	CHEMBL110716
8.22	IC50	6	nM	CHEMBL321903
8.22	IC50	6	nM	CHEMBL316549
8.22	IC50	6	nM	CHEMBL108325
8.22	IC50	6	nM	CHEMBL110655
8.22	IC50	6	nM	CHEMBL108519
8.22	IC50	6	nM	CHEMBL106200
8.15	IC50	7	nM	CHEMBL108207
8.15	IC50	7	nM	CHEMBL3814077
8.15	IC50	7	nM	CHEMBL110597
8.15	IC50	7	nM	CHEMBL321483
8.11	IC50	7.7	nM	CHEMBL3690093
8.10	IC50	8	nM	CHEMBL324436
8.10	IC50	8	nM	CHEMBL4101186
8.10	IC50	8	nM	CHEMBL4063918
8.10	IC50	8	nM	CHEMBL320708
8.05	IC50	9	nM	CHEMBL322051
8.05	IC50	9	nM	CHEMBL106756
8.00	IC50	10	nM	CHEMBL105834
8.00	IC50	10	nM	CHEMBL322794
8.00	IC50	10	nM	CHEMBL49896
8.00	IC50	10	nM	CHEMBL3644849

PubChem BioAssay actives

268 with measured affinity, of 387 total; 50 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
2-[4-(3-fluorophenyl)piperidine-1-carbonyl]-4-(2-methoxyethyl)-3-methyl-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0002	uM
[4-[(4-tert-butylcyclohexanecarbonyl)amino]phenyl] N-morpholin-4-ylcarbamate	90857: Inhibition of human recombinant hormone sensitive lipase.	ic50	0.0010	uM
4-butyl-3-methyl-2-(4-methylpiperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0010	uM
2-[4-(3-methoxyphenyl)piperazine-1-carbonyl]-3-methyl-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0010	uM
[5-chloro-2-[[6-[4-(trifluoromethyl)phenoxy]pyridine-3-carbonyl]amino]phenyl]boronic acid	1432867: Inhibition of recombinant human HSL expressed in baculovirus infected sf9 cells using PNPB as substrate after 5 mins by spectrophotometric method	ic50	0.0020	uM
3-methyl-2-(piperidine-1-carbonyl)-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0020	uM
3-methyl-4-(2-phenoxyethyl)-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0020	uM
N,3-dimethyl-5-oxo-4-propan-2-yl-N-(thiophen-2-ylmethyl)-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0020	uM
3-methyl-2-[(3S)-3-methylpiperidine-1-carbonyl]-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0030	uM
[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl] N-(3,4-dihydro-1H-isoquinolin-2-yl)carbamate	90857: Inhibition of human recombinant hormone sensitive lipase.	ic50	0.0030	uM
4-(2-ethoxyethyl)-3-methyl-2-(4-methylpiperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0030	uM
3-methyl-2-(4-methylpiperidine-1-carbonyl)-4-(2-methylpropyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0030	uM
4-cyclohexyl-3-methyl-2-(4-methylpiperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0040	uM
N-[(2-fluorophenyl)methyl]-N,3-dimethyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0040	uM
3-methyl-4-(2-methylpropyl)-2-(4-phenylpiperidine-1-carbonyl)-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0040	uM
4-(2-methoxyethyl)-3-methyl-2-[4-(3-methylphenyl)piperidine-1-carbonyl]-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0040	uM
2-[4-(3-fluorophenyl)piperidine-1-carbonyl]-3-methyl-4-propan-2-yl-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0040	uM
N-(furan-2-ylmethyl)-N,3-dimethyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0040	uM
benzyl 2-[4-(morpholin-4-ylcarbamoyloxy)phenyl]acetate	90857: Inhibition of human recombinant hormone sensitive lipase.	ic50	0.0050	uM
3-methyl-4-(2-methylpropyl)-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0050	uM
4-benzyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0050	uM
N-[(3-fluorophenyl)methyl]-N,3-dimethyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0050	uM
4-(2-methoxyethyl)-3-methyl-2-(4-phenylpiperidine-1-carbonyl)-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0050	uM
N-benzyl-N,3-dimethyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0050	uM
4-(4-chlorophenyl)sulfanyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
3-methyl-2-(4-methylpiperidine-1-carbonyl)-4-(thian-4-yl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
3-methyl-4-phenylsulfanyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
3-methyl-2-(4-methylpiperidine-1-carbonyl)-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
4-cyclopentyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
ethyl 1-(3-methyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carbonyl)piperidine-4-carboxylate	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
3-methyl-2-(4-phenylpiperazine-1-carbonyl)-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0060	uM
[2-[[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methoxy]phenyl]boronic acid	1306885: Inhibition of recombinant human HSL expressed in Sf9 insect cells using PNPB as substrate measured after 5 mins by spectrophotometric method	ic50	0.0070	uM
4-butyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0070	uM
N,3-dimethyl-5-oxo-N-phenyl-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0070	uM
2-(3,3-dimethylpiperidine-1-carbonyl)-3-methyl-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0070	uM
[5-chloro-2-[2-oxo-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]piperidin-1-yl]ethyl]phenyl]boronic acid	1461939: Inhibition of recombinant human HSL expressed in baculovirus infected sf9 insect cells using PNPB as substrate after 5 mins by spectrophotometric analysis	ic50	0.0080	uM
N-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide	1432867: Inhibition of recombinant human HSL expressed in baculovirus infected sf9 cells using PNPB as substrate after 5 mins by spectrophotometric method	ic50	0.0080	uM
4-cyclopentyl-3-methyl-2-(4-phenylpiperidine-1-carbonyl)-1,2-oxazol-5-one	3416: Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	ic50	0.0080	uM
3-methyl-4-propan-2-yl-2-(thiomorpholine-4-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0080	uM
N-cyclohexyl-N,3-dimethyl-5-oxo-4-propan-2-yl-1,2-oxazole-2-carboxamide	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0090	uM
[4-(cyclohexanecarbonylamino)phenyl] N-morpholin-4-ylcarbamate	90857: Inhibition of human recombinant hormone sensitive lipase.	ic50	0.0100	uM
4-(2-methoxyethyl)-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0100	uM
3-methyl-2-(piperidine-1-carbonyl)-4-(thian-4-yl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0110	uM
4-cyclohexyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0110	uM
3-methyl-2-(4-phenylpiperidine-1-carbonyl)-4-propan-2-yl-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0120	uM
[5-fluoro-2-[[6-[4-(trifluoromethyl)phenoxy]pyridine-3-carbonyl]amino]phenyl]boronic acid	1432867: Inhibition of recombinant human HSL expressed in baculovirus infected sf9 cells using PNPB as substrate after 5 mins by spectrophotometric method	ic50	0.0130	uM
3,4-dimethyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0130	uM
N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide	1432867: Inhibition of recombinant human HSL expressed in baculovirus infected sf9 cells using PNPB as substrate after 5 mins by spectrophotometric method	ic50	0.0140	uM
4-tert-butyl-3-methyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0140	uM
3-methyl-4-phenyl-2-(piperidine-1-carbonyl)-1,2-oxazol-5-one	90855: Inhibition of human recombinant hormone sensitive lipase (HSL)	ic50	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol S	increases expression	3
nuciferine	decreases expression, decreases reaction	2
cobaltous chloride	decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Dietary Carbohydrates	decreases expression, affects cotreatment, affects expression	2
Niacin	decreases activity, decreases expression	2
Palmitic Acid	decreases expression, decreases reaction	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
retinol palmitate	increases hydrolysis, decreases reaction	1
mono-(2-ethylhexyl)phthalate	increases expression	1
2-chloroethyl ethyl sulfide	increases phosphorylation	1
tuberostemonine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	increases expression	1
bisphenol B	increases expression	1
chiglitazar	increases expression	1
dorsomorphin	decreases expression, decreases reaction	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Tenofovir	affects expression	1
Rosiglitazone	increases expression	1
Sunitinib	decreases expression	1
Cyclic AMP	increases activity	1
Adenosine Triphosphate	increases activity	1
Cisplatin	affects cotreatment, increases expression	1
Deferoxamine	decreases expression	1
Dexamethasone	increases expression	1

ChEMBL screening assays

27 unique, capped per target: 25 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3606467	Binding	Inhibition of HSL (unknown origin)	Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials. — J Med Chem
CHEMBL615539	Functional	Inhibition of forskolin-stimulated lipolysis in differentiated 3T3-L1 cells	In vitro SAR of (5-(2H)-isoxazolonyl) ureas, potent inhibitors of hormone-sensitive lipase. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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