HILPDA

Summary

HILPDA (hypoxia inducible lipid droplet associated, HGNC:28859) is a protein-coding gene on chromosome 7q32.1, encoding Hypoxia-inducible lipid droplet-associated protein (Q9Y5L2). Increases intracellular lipid accumulation.

Enables signaling receptor binding activity. Involved in several processes, including autocrine signaling; cellular response to hypoxia; and positive regulation of lipid storage. Located in several cellular components, including cell surface; lipid droplet; and secretory granule. Implicated in colorectal cancer and hepatocellular carcinoma. Biomarker of colorectal cancer and hepatocellular carcinoma.

Source: NCBI Gene 29923 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_013332

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28859
Approved symbol	HILPDA
Name	hypoxia inducible lipid droplet associated
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21076, HIG-2, HIG2
Ensembl gene	ENSG00000135245
Ensembl biotype	protein_coding
OMIM	617905
Entrez	29923

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000257696, ENST00000435296, ENST00000466473, ENST00000481454, ENST00000916177, ENST00000916178

RefSeq mRNA: 2 — MANE Select: NM_013332 NM_001098786, NM_013332

CCDS: CCDS5802

Canonical transcript exons

ENST00000257696 — 2 exons

Exon	Start	End
ENSE00000919490	128457201	128458418
ENSE00001811782	128455878	128456023

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.0367 / max 508.8813, expressed in 1771 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80920	21.5778	1741
80921	3.8519	1256
80919	2.6069	1402

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	99.93	gold quality
pericardium	UBERON:0002407	99.70	gold quality
lower esophagus mucosa	UBERON:0035834	99.50	gold quality
saphenous vein	UBERON:0007318	98.96	gold quality
type B pancreatic cell	CL:0000169	97.52	gold quality
cartilage tissue	UBERON:0002418	97.09	gold quality
nipple	UBERON:0002030	97.05	gold quality
esophagus squamous epithelium	UBERON:0006920	95.75	gold quality
oocyte	CL:0000023	95.09	gold quality
epithelium of esophagus	UBERON:0001976	95.05	gold quality
esophagus mucosa	UBERON:0002469	94.26	gold quality
adipose tissue	UBERON:0001013	93.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.00	gold quality
medial globus pallidus	UBERON:0002477	92.88	gold quality
trachea	UBERON:0003126	92.75	gold quality
mammalian vulva	UBERON:0000997	92.53	gold quality
connective tissue	UBERON:0002384	92.50	gold quality
olfactory bulb	UBERON:0002264	92.28	silver quality
globus pallidus	UBERON:0001875	92.27	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.90	gold quality
trigeminal ganglion	UBERON:0001675	91.85	gold quality
peritoneum	UBERON:0002358	91.65	gold quality
omental fat pad	UBERON:0010414	91.65	gold quality
secondary oocyte	CL:0000655	91.38	gold quality
pharyngeal mucosa	UBERON:0000355	91.05	gold quality
squamous epithelium	UBERON:0006914	90.85	gold quality
upper leg skin	UBERON:0004262	90.75	gold quality
tongue squamous epithelium	UBERON:0006919	90.24	gold quality
dorsal root ganglion	UBERON:0000044	89.73	gold quality
lateral globus pallidus	UBERON:0002476	89.69	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	4.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, SOX11

miRNA regulators (miRDB)

31 targeting HILPDA, 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-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-8078	98.32	65.73	361
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-4436B-5P	96.71	68.37	1346
HSA-MIR-632	96.08	67.17	798
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-4781-3P	95.78	65.66	572
HSA-MIR-4524B-3P	95.52	64.12	964
HSA-MIR-103B	95.51	66.85	441

Literature-anchored findings (GeneRIF, showing 20)

• may be used as a marker for early detection of ovarian clear cell adenocarcinoma (PMID:20134266)
• HIG2 was up-regulated by hypoxia and HIF inducers in all cell types and mouse organs investigated and abundantly expressed in renal clear-cell carcinomas (PMID:20624928)
• Data show that DBN1, SETMAR and HIG2 are direct transcriptional targets of the SOX11 protein. (PMID:21124928)
• there was no significant relationship between HIG2 expression and age, clinical stage and histology in either cervical cancer or endometrial cancer. (PMID:21614900)
• Data indicate that HIG2 (hypoxia-inducible gene 2) is a HIF-1alpha target in regulating cell survival during hypoxia. (PMID:23916472)
• data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion. (PMID:24876382)
• Study showed for the first time that HIG-2 and SOX11 mutually co-regulate each other, and that HIG-2 and SOX11 knock-down promote increased proliferation in a non-synergistic manner in primary mantle cell lymphoma cells. (PMID:26757780)
• Authors conclude that HIG2 is overexpressed in GBM and upregulated by hypoxia. (PMID:27329597)
• hypoxia-inducible lipid droplet-associated protein inhibits adipose triglyceride lipase (PMID:29326160)
• Expression changes in secreted frizzled-related protein 2, stearoyl-CoA desaturase, and hypoxia inducible lipid droplet-associated (HILPDA) with weight loss were confirmed by reverse transcription quantitative polymerase chain reaction. Dietary weight loss induces significant changes in the expression of genes implicated in lipid metabolism (SCD and HILPDA) and WNT-signaling (SFRP2) in subcutaneous adipose tissue. (PMID:30884788)
• In renal clear-cell carcinomas, HIF-2alpha selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). (PMID:30962421)
• HIG2 activates the STAT3 signaling pathway in NK cells by promoting IL-10 release by HCC cells, thereby inhibiting the killing activity of NK cells, and subsequently promoting the recurrence and metastasis of HCC. (PMID:31142329)
• Lipidomic analysis revealed not only quantitative but also qualitative differences in the glycerolipid and phospholipid profile of HILPDA wild-type and knockout cells, indicating additional HILPDA functions affecting lipid metabolism. (PMID:31308147)
• Hypoxia, hypoxia-inducible gene 2 (HIG2)/HILPDA, and intracellular lipolysis in cancer. (PMID:32818550)
• IRF1 promotes the chondrogenesis of human adipose-derived stem cells through regulating HILPDA. (PMID:36933274)
• Downregulation of fatty acid oxidation led by Hilpda increases G2/M arrest/delay-induced kidney fibrosis. (PMID:36990128)
• HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia. (PMID:37061197)
• HILPDA-mediated lipidomic remodelling promotes radiotherapy resistance in nasopharyngeal carcinoma by accelerating mitophagy. (PMID:37552373)
• Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma. (PMID:38335255)
• FOXS1 acts as an oncogene and induces EMT through FAK/PI3K/AKT pathway by upregulating HILPDA in prostate cancer. (PMID:38780613)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hilpda	ENSMUSG00000043421
rattus_norvegicus	Hilpda	ENSRNOG00000070930

Protein

Protein identifiers

Hypoxia-inducible lipid droplet-associated protein — Q9Y5L2 (reviewed: Q9Y5L2)

Alternative names: Hypoxia-inducible gene 2 protein

All UniProt accessions (1): Q9Y5L2

UniProt curated annotations — full annotation on UniProt →

Function. Increases intracellular lipid accumulation. Stimulates expression of cytokines including IL6, MIF and VEGFA. Enhances cell growth and proliferation.

Subcellular location. Lipid droplet. Secreted. Membrane.

Tissue specificity. Highly expressed in renal cell carcinoma cells but barely detectable in adjacent normal kidney tissue. Detected in some cervical and endometrial cancers. Expression also detected in fetal kidney with little or no expression observed in normal adult heart, liver, lung, pancreas, prostate or spinal cord (at protein level).

Induction. By hypoxia but highly abundant under normoxic conditions (at protein level).

RefSeq proteins (2): NP_001092256, NP_037464* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026190	Hipoxia_HILPDA	Family

Pfam: PF15220

UniProt features (10 total): mutagenesis site 3, region of interest 2, chain 1, transmembrane region 1, compositionally biased region 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5L2-F1	72.97	0.38

Functional residue map

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

Post-translational modifications (1): 44

Mutagenesis-validated functional residues (3):

Position	Phenotype
8–9	loss of targeting to lipid droplets and elimination of protein.
41	no effect on lipid droplet targeting or protein expression; when associated with k-44.
44	no effect on lipid droplet targeting or protein expression; when associated with k-41.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8964572	Lipid particle organization

MSigDB gene sets: 224 (showing top): GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_YELLOW_DN, GOBP_REGULATION_OF_LIPID_STORAGE, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, MENSE_HYPOXIA_UP, KENNY_CTNNB1_TARGETS_UP, GOCC_CELL_SURFACE, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, NAGASHIMA_NRG1_SIGNALING_UP, TTGGGAG_MIR150, GOBP_CELL_CELL_SIGNALING, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS

GO Biological Process (6): positive regulation of cytokine production (GO:0001819), positive regulation of cell population proliferation (GO:0008284), positive regulation of lipid storage (GO:0010884), lipid droplet organization (GO:0034389), autocrine signaling (GO:0035425), cellular response to hypoxia (GO:0071456)

GO Molecular Function (3): signaling receptor binding (GO:0005102), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), lipid droplet (GO:0005811), cytosol (GO:0005829), cell surface (GO:0009986), membrane (GO:0016020), secretory granule (GO:0030141), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
positive regulation of cellular process	2
protein binding	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
cell population proliferation	1
regulation of cell population proliferation	1
regulation of lipid storage	1
lipid storage	1
positive regulation of lipid localization	1
organelle organization	1
cell-cell signaling	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
molecular adaptor activity	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HILPDA	FZD10	Q9ULW2	700
HILPDA	PNPLA2	Q96AD5	683
HILPDA	CIDEC	Q96AQ7	620
HILPDA	G0S2	P27469	525
HILPDA	PLIN2	Q99541	509
HILPDA	ABHD5	Q8WTS1	507
HILPDA	CA9	Q16790	448
HILPDA	PLIN1	O60240	445
HILPDA	EGLN3	Q9H6Z9	431
HILPDA	SPAG4	Q9NPE6	430
HILPDA	MMD	Q15546	416
HILPDA	PLIN3	O60664	407
HILPDA	HIF1A	Q16665	400
HILPDA	EPAS1	Q99814	398
HILPDA	FABP5	Q01469	375
HILPDA	ANGPTL4	Q9BY76	375

IntAct

6 interactions, top by confidence:

A	B	Type	Score
HILPDA	GET3	psi-mi:“MI:0915”(physical association)	0.560
FZD10	HILPDA	psi-mi:“MI:0915”(physical association)	0.400
HILPDA	FZD10	psi-mi:“MI:0915”(physical association)	0.400
HILPDA	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (5): HILPDA (Two-hybrid), HILPDA (Two-hybrid), HILPDA (Phenotypic Suppression), HILPDA (Affinity Capture-RNA), HILPDA (Affinity Capture-RNA)

ESM2 similar proteins: A0A5F9ZH02, A4IHD1, A4QJD5, A4QJL9, A6MVU6, B0YPP8, C0H3S8, G2TRL0, O78514, P03783, P0CA13, P11888, P18024, P19720, P22666, P26460, P29661, P35091, P38458, P39495, P43566, P46879, P48105, P50943, P51390, P86994, P89035, P92528, Q06FN9, Q06J12, Q12160, Q1CVG0, Q1XD97, Q2JLQ8, Q31652, Q3V0X1, Q4G381, Q5N554, Q61979, Q62649

Diamond homologs: Q9JLS0, Q9Y5L2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

177 predictions. Top by Δscore:

Variant	Effect	Δscore
7:128457199:AG:A	acceptor_gain	0.9800
7:128457200:GG:G	acceptor_gain	0.9800
7:128456021:G:GT	donor_gain	0.9700
7:128456022:AGG:A	donor_loss	0.9700
7:128456023:GGT:G	donor_loss	0.9700
7:128456024:G:GA	donor_loss	0.9700
7:128456025:T:G	donor_loss	0.9700
7:128457197:TCAG:T	acceptor_loss	0.9600
7:128457199:A:G	acceptor_loss	0.9600
7:128456026:GAGCG:G	donor_loss	0.9500
7:128456020:GGAG:G	donor_gain	0.9200
7:128457199:A:AG	acceptor_gain	0.9200
7:128457200:G:GG	acceptor_gain	0.9200
7:128457333:GA:G	acceptor_gain	0.9100
7:128457333:G:C	acceptor_gain	0.9000
7:128456021:GAG:G	donor_gain	0.8800
7:128457198:CAGGG:C	acceptor_gain	0.8800
7:128457200:GGGTC:G	acceptor_gain	0.8700
7:128455905:CTCCG:C	donor_loss	0.8600
7:128455907:CCGGT:C	donor_loss	0.8600
7:128455908:CGG:C	donor_loss	0.8600
7:128455910:GTG:G	donor_loss	0.8600
7:128455911:T:TT	donor_loss	0.8600
7:128455912:GAGTT:G	donor_loss	0.8600
7:128455913:A:AT	donor_loss	0.8500
7:128455914:G:C	donor_loss	0.8500
7:128455910:G:GG	donor_gain	0.8300
7:128455943:GCTT:G	donor_gain	0.8300
7:128457199:AGGG:A	acceptor_gain	0.8100
7:128457247:GAGGA:G	donor_gain	0.8100

AlphaMissense

396 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:128457300:G:A	G11D	0.853
7:128457299:G:C	G11R	0.845
7:128457290:T:G	Y8D	0.744
7:128457326:T:C	F20L	0.722
7:128457328:C:A	F20L	0.722
7:128457328:C:G	F20L	0.722
7:128457315:T:G	L16R	0.707
7:128457315:T:C	L16P	0.676
7:128457309:T:G	L14R	0.671
7:128457318:T:G	L17R	0.666
7:128457318:T:A	L17H	0.648
7:128457309:T:C	L14P	0.642
7:128457315:T:A	L16Q	0.605
7:128457324:T:A	I19N	0.591
7:128457309:T:A	L14Q	0.580
7:128457299:G:T	G11C	0.573
7:128457318:T:C	L17P	0.564

dbSNP variants (sampled 300 via entrez): RS1000571520 (7:128458343 T>G), RS1000574946 (7:128458729 C>T), RS1001792425 (7:128457997 C>G,T), RS1002306584 (7:128454086 C>G), RS1002560289 (7:128455119 A>G,T), RS1003688040 (7:128456896 A>G), RS1004597401 (7:128454894 G>A), RS1005094456 (7:128458024 C>A,T), RS1005195178 (7:128454143 T>G), RS1005639408 (7:128454476 A>C), RS1006226546 (7:128455738 C>G), RS1006269723 (7:128455908 C>G,T), RS1006291832 (7:128455215 T>C), RS1007058558 (7:128457227 G>A), RS1007202238 (7:128456565 A>G)

Disease associations

OMIM: gene MIM:617905 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	decreases reaction, increases expression	3
Benzo(a)pyrene	increases methylation, increases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, decreases expression	1
alpha phellandrene	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chloride	increases expression, decreases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases reaction, increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
chloroquine diphosphate	decreases expression	1
1,10-phenanthroline	increases expression	1
cobalt sulfate	increases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	increases expression	1
resorcinol	increases expression	1
pentanal	decreases expression	1
celastrol	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
gedunin	decreases expression	1
motexafin gadolinium	increases expression, affects cotreatment	1
vandetanib	increases expression	1
candoxin	decreases expression	1

Clinical trials (associated diseases)

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