ENHO

Summary

ENHO (energy homeostasis associated, HGNC:24838) is a protein-coding gene on chromosome 9p13.3, encoding Adropin (Q6UWT2). Involved in the regulation of glucose homeostasis and lipid metabolism.

Predicted to enable hormone activity. Predicted to be involved in positive regulation of Notch signaling pathway. Predicted to be located in extracellular region. Predicted to be active in plasma membrane.

Source: NCBI Gene 375704 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_198573

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24838
Approved symbol	ENHO
Name	energy homeostasis associated
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ470
Ensembl gene	ENSG00000168913
Ensembl biotype	protein_coding
OMIM	618556
Entrez	375704

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000399775, ENST00000876890

RefSeq mRNA: 1 — MANE Select: NM_198573 NM_198573

CCDS: CCDS43795

Canonical transcript exons

ENST00000399775 — 2 exons

Exon	Start	End
ENSE00001223948	34521043	34521856
ENSE00001540144	34522777	34522990

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 98.91.

FANTOM5 (CAGE): breadth broad, TPM avg 4.6136 / max 152.7352, expressed in 479 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100514	3.3281	395
100517	0.9213	329
100516	0.2094	109
100515	0.1548	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amygdala	UBERON:0001876	98.91	gold quality
putamen	UBERON:0001874	98.82	gold quality
right frontal lobe	UBERON:0002810	98.76	gold quality
nucleus accumbens	UBERON:0001882	98.75	gold quality
caudate nucleus	UBERON:0001873	98.59	gold quality
hypothalamus	UBERON:0001898	98.53	gold quality
anterior cingulate cortex	UBERON:0009835	98.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.44	gold quality
substantia nigra	UBERON:0002038	98.12	gold quality
prefrontal cortex	UBERON:0000451	98.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.65	gold quality
midbrain	UBERON:0001891	97.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.34	gold quality
lateral globus pallidus	UBERON:0002476	97.09	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.00	gold quality
spinal cord	UBERON:0002240	96.95	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.80	gold quality
cerebellar hemisphere	UBERON:0002245	96.79	gold quality
cerebellar cortex	UBERON:0002129	96.65	gold quality
ventricular zone	UBERON:0003053	96.46	gold quality
frontal cortex	UBERON:0001870	96.34	gold quality
neocortex	UBERON:0001950	96.34	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.98	gold quality
cerebellum	UBERON:0002037	95.74	gold quality
cerebral cortex	UBERON:0000956	95.49	gold quality
substantia nigra pars compacta	UBERON:0001965	95.41	gold quality
temporal lobe	UBERON:0001871	95.39	gold quality
Ammon’s horn	UBERON:0001954	95.08	gold quality
brain	UBERON:0000955	94.68	gold quality
ventral tegmental area	UBERON:0002691	94.67	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	22.14
E-CURD-112	yes	14.33
E-GEOD-84465	yes	11.15
E-ANND-3	no	0.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1H2, NR1H3

miRNA regulators (miRDB)

39 targeting ENHO, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-505-5P	97.01	65.54	778

Literature-anchored findings (GeneRIF, showing 40)

• Adropin is the name given to the secreted peptide encoded by the ORF in C9orf165. In mice, it is abundant in liver where it is regulated by dietary macronutrients. Adropin regulates expression of genes involved in lipogenesis and adipogenesis. (PMID:19041763)
• Adropin has an endothelial protective function mediated via upregulation of eNOS expression through the VEGFR2-PI3K-Akt and VEGFR2-ERK1/2 pathways. Adropin therapy may thus be useful for limiting diseases characterized by endothelial dysfunction. (PMID:20837912)
• a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3-kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. (PMID:20837912)
• Plasma adropin levels are regulated dietary macronutrients increasing with dietary fat content. Fasting suppresses plasma adropin. Adropin’s actions are required for preventing insulin resistance, dyslipidemia and impaired glucose tolerance. (PMID:22318315)
• Although males exhibit higher adropin levels that are reduced by obesity, aging and markers of insulin resistance are associated with low plasma adropin irrespective of sex. (PMID:22872690)
• Plasma adropin levels were examined in 45 men and 85 woman. Adropin levels are higher in men than woman. Obesity is associated with low adropin levels in men. Aging and metabolic risk factors are associated with low adropin levels, irrespective of sex. (PMID:22872690)
• The mean maternal and cord serum adropin in a gestational diabetes mellitus group were significantly lower than those of control women (P=0.01 and P<0.001, respectively). (PMID:23314506)
• Adropin is an independent risk factor for cardiac syndrome X (CSX). (PMID:23356444)
• Plasma adropin levels were found to be a new marker for diagnosing endothelial dysfunction in type 2 diabetes mellitus. (PMID:24113736)
• cord blood adropin levels were positively correlated with gestational age and placental weight but not with other fetal growth parameters. (PMID:24284417)
• Assessment of serum adropin concentrations may provide a reliable indicator of fatty liver disease in obese adolescents (PMID:24468600)
• decreased serum adropin levels are associated with the presence of acute myocardial infarction in coronary artery disease patients (PMID:24731968)
• Release of adropin in the fed condition regulates fuel selection in skeletal muscle, promoting glucose oxidation over fat oxidation. The molecular mechanisms of adropin’s effects involve acetylation (suggesting inhibition) of the transcriptional co-activator PGC1alpha, reducing PDK4 and CPT1B activity. Increased PGC1alpha acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC1alpha deacetylase. (PMID:24848071)
• Adropin levels are lower in patients with late saphenous vein graft occlusion and these reduced adropin levels, together with other factors, may lead to saphenous vein graft occlusion (PMID:25282140)
• Adropin as a novel energy factor likely has the ability to regulate blood pressure (PMID:25913544)
• Serum adropin levels were significantly lower in obese children; however, there was no correlation between serum adropin levels and blood pressure variables. (PMID:26030787)
• Circulating adropin levels were determined lower in patients with endometrial cancer than in a control group. (PMID:26172926)
• The adropin levels of metabolic syndrome, obesity, and control groups also showed no difference (PMID:26226125)
• Serum adropin level was negatively correlated with carotid beta-stiffness and positively correlated with plasma NOx level and cardiorespiratory fitness (PMID:26371163)
• Lipids originating either from the diet or from endogenous production appear to positively affect plasma adropin concentrations in humans. (PMID:26435060)
• High adropin expression is associated with polycystic ovary syndrome. (PMID:26969461)
• There were no significant differences among the groups of systemic sclerosis (SSc) and controls in terms of ENHO gene expressions. There was no significant difference between the limited and diffuse cutaneous subtypes of SSc in terms of serum adropin level and ENHO gene expression. Moreover, serum adropin level and ENHO gene expression were not associated with the disease activity and severity indexes. (PMID:27079850)
• Enho mutations plays a critical role in activating endothelial cells during neutrophil recruitment and neutrophil-endothelium cell interactions under IL-1 and TNF-alpha-induced vascular inflammation and increases susceptibility to MPOANCA associated lung injury. (PMID:27333037)
• In HD patients, lower plasma adropin concentration is associated with dyslipidemia. Major homozygosity of RXRA seems to have an opposite effect on plasma adropin compared with that of ENHO rs2281997 (PMID:27449397)
• Serum adropin concentrations are negatively associated with renal function. (PMID:27546995)
• Data suggest that serum adropin (ENHO) levels in normal, overweight, and obese adults negatively correlate with vascular stiffness (using common carotid artery) and adiposity (using abdominal visceral fat), and positively correlate with plasma nitric oxide levels (using nitrite/nitrate) and cardiorespiratory fitness; aerobic exercise training up-regulates serum adropin. (PMID:27897440)
• Plasma adropin levels are not consistency associated with body composition and no association with lipid variables amongst Taiwanese adolescents. The role of adropin in the development of obesity is still not clear, and further studies are need especially for children. (PMID:28363705)
• An increase in maternal serum adropin level was found in preeclampsia. (PMID:28501281)
• significant association between maternal and umbilical adropin levels and the presence and severity of preeclampsia (PMID:28672759)
• Data suggest that serum and follicular fluid levels of adropin are down-regulated in women with PCOS (polycystic ovary syndrome) compared with control subjects; also, follicular fluid levels of adropin are lower than serum levels of adropin. (PMID:28937295)
• Analysis of midluteal endometrial biopsies revealed an inverse correlation between endometrial EOGT and ENHO expression and body mass index. Obesity impairs the EOGT-adropin axis in decidual cells, which in turn points toward a mechanistic link between metabolic disorders and adverse pregnancy outcome. (PMID:29244071)
• Adropin is coupled with biological clock activity. In mouse liver, ENHO expression has a diurnal rhythm that peaks at the end of maximal nutrient intake in the dark. The nuclear receptors ROR-alpha/gamma and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. (PMID:29331507)
• Serum adropin concentrations are decreased in Chinese T2DM patients, especially those overweight/obese. Adropin, associated with glucolipid homeostasis and insulin sensitivity, may implicate in the pathogenesis of T2DM. (PMID:29669965)
• Although the ENHO[energy homeostasis-associated gene] gene expression is increased, serum adropin level is not altered in RA. Similarly, adropin seems not to be associated with SLE. However, the potential link between adropin and inflammatory diseases need to be tested by further studies. (PMID:30141839)
• The highest adropin concentration was found in patients with P-Ch C (11.7+/-5.7 ng/ml) cirrhosis. (PMID:30260179)
• ENHO, RXRA, and LXRA polymorphisms and dyslipidemia, related comorbidities and survival in hemodialysis patients have been reported. (PMID:30413149)
• Serum and vitreous adropin concentrations are negatively associated with the presence of diabetic retinopathy (PMID:30514096)
• lower serum concentration significantly associated with hypertensive disorders complicating pregnancy (PMID:31438729)
• Serum adropin levels are reduced in patients with inflammatory bowel diseases. (PMID:32518265)
• Lower adropin expression is associated with oxidative stress and severity of nonalcoholic fatty liver disease. (PMID:32810635)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Enho	ENSMUSG00000028445
rattus_norvegicus	Enho	ENSRNOG00000043300

Protein

Protein identifiers

Adropin — Q6UWT2 (reviewed: Q6UWT2)

Alternative names: Energy homeostasis-associated protein

All UniProt accessions (1): Q6UWT2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of glucose homeostasis and lipid metabolism.

Subcellular location. Secreted.

Tissue specificity. Expressed in liver and brain.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UWT2-1	1	yes
Q6UWT2-2	2

RefSeq proteins (1): NP_940975* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR034461	Adropin	Family

UniProt features (5 total): signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWT2-F1	74.43	0.39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 77 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, SP3_Q3, AREB6_03, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, AREB6_01, chr9p13, HEN1_01, GOBP_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, AACTTT_UNKNOWN, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_ENERGY_HOMEOSTASIS, DBP_Q6, GOMF_SIGNALING_RECEPTOR_BINDING, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP

GO Biological Process (5): positive regulation of Notch signaling pathway (GO:0045747), energy homeostasis (GO:0097009), MAPK cascade (GO:0000165), G protein-coupled receptor signaling pathway (GO:0007186), glucose homeostasis (GO:0042593)

GO Molecular Function (1): hormone activity (GO:0005179)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
multicellular organismal-level homeostasis	1
intracellular signaling cassette	1
G protein-coupled receptor activity	1
signal transduction	1
carbohydrate homeostasis	1
receptor ligand activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENHO	GPR19	Q15760	902
ENHO	FNDC5	Q8NAU1	583
ENHO	FAM219A	Q8IW50	546
ENHO	RPP25L	Q8N5L8	527
ENHO	DCTN3	O75935	470
ENHO	C10orf120	Q5SQS8	461
ENHO	INS	P01308	448
ENHO	CNTN6	Q9UQ52	446
ENHO	PDK4	Q16654	417
ENHO	NOS3	P29474	411
ENHO	FITM1	A5D6W6	401
ENHO	NUCB2	P80303	390
ENHO	FGF21	Q9NSA1	380
ENHO	SPX	Q9BT56	377
ENHO	ANGPTL4	Q9BY76	376

IntAct

0 interactions, top by confidence:

BioGRID (1): ENHO (Negative Genetic)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GSZ0, A0A1B0GVT2, A0A590UK83, A0PK05, A2VDU1, A2VE22, A4QNL6, A5D7B5, A5D992, O43609, O75324, P0DKX4, P29414, P61807, P61808, Q0VFM5, Q15053, Q16655, Q17Q87, Q1L0X2, Q2KIK3, Q2TBG9, Q3MHM8, Q498C7, Q4V921, Q58CU5, Q5RBD8, Q5RF07, Q5RGQ8, Q64448, Q6UWT2, Q80ZU4, Q8BGN6, Q8BUM6, Q8C3K5, Q8C817, Q8K1D8, Q8N6S5, Q91VT8

Diamond homologs: A2VE22, Q6UWT2, Q8K1D8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

145 predictions. Top by Δscore:

Variant	Effect	Δscore
9:34522627:ATCC:A	donor_gain	0.9600
9:34522771:TCTTA:T	donor_loss	0.9600
9:34522772:CTTA:C	donor_loss	0.9600
9:34522773:TTA:T	donor_loss	0.9600
9:34522774:TACC:T	donor_loss	0.9600
9:34522775:ACCTG:A	donor_loss	0.9600
9:34521855:GCCT:G	acceptor_loss	0.8900
9:34521857:C:CA	acceptor_loss	0.8900
9:34521858:T:A	acceptor_loss	0.8900
9:34522658:T:TA	donor_gain	0.8900
9:34521857:C:CC	acceptor_gain	0.8800
9:34522775:A:AC	donor_gain	0.8800
9:34522776:C:CC	donor_gain	0.8800
9:34521853:GAGCC:G	acceptor_gain	0.8400
9:34521860:T:TC	acceptor_gain	0.8200
9:34522627:ATC:A	donor_gain	0.8100
9:34523007:T:TA	donor_gain	0.8100
9:34521860:T:C	acceptor_gain	0.8000
9:34521872:A:T	acceptor_gain	0.8000
9:34521868:A:C	acceptor_gain	0.7800
9:34521866:G:C	acceptor_gain	0.7400
9:34522061:G:C	donor_gain	0.7400
9:34522533:C:CT	donor_gain	0.7400
9:34522534:T:TT	donor_gain	0.7400
9:34521852:TGAGC:T	acceptor_gain	0.7300
9:34522532:TC:T	donor_gain	0.7200
9:34521854:AGCCT:A	acceptor_gain	0.7000
9:34521855:GCCTG:G	acceptor_gain	0.7000
9:34521868:A:AC	acceptor_gain	0.7000
9:34522039:TGGC:T	donor_gain	0.7000

AlphaMissense

485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:34521617:A:G	W27R	0.948
9:34521617:A:T	W27R	0.948
9:34521647:C:G	G17R	0.945
9:34521638:C:G	G20R	0.943
9:34521646:C:T	G17D	0.939
9:34521655:A:T	V14D	0.919
9:34521637:C:T	G20D	0.917
9:34521653:A:G	C15R	0.913
9:34521674:C:G	G8R	0.877
9:34521674:C:T	G8R	0.877
9:34521628:A:C	L23R	0.866
9:34521658:A:T	I13N	0.859
9:34521619:A:T	L26H	0.853
9:34521619:A:C	L26R	0.835
9:34521643:A:T	L18H	0.833
9:34521661:G:T	A12D	0.825
9:34521667:A:T	L10H	0.803
9:34521628:A:T	L23Q	0.791
9:34521674:C:A	G8W	0.777
9:34521692:C:G	G2R	0.776
9:34521692:C:T	G2R	0.776
9:34521613:A:T	V28D	0.773
9:34521692:C:A	G2W	0.772
9:34521622:A:C	L25R	0.768
9:34521643:A:C	L18R	0.766
9:34521628:A:G	L23P	0.761
9:34521605:A:G	C31R	0.753
9:34521607:A:T	L30H	0.752
9:34521643:A:G	L18P	0.747
9:34521625:A:C	L24R	0.730

dbSNP variants (sampled 300 via entrez): RS1000202179 (9:34522299 T>C), RS1000599024 (9:34521114 T>G), RS1000888326 (9:34522091 G>A,T), RS1002723217 (9:34524520 C>A,G,T), RS1002774043 (9:34524853 T>G), RS1003372470 (9:34523841 T>A), RS1004388010 (9:34522741 T>G), RS1004440370 (9:34523269 C>T), RS1005473784 (9:34523431 G>A,T), RS1005855278 (9:34523801 G>A,T), RS1006620315 (9:34523375 C>G,T), RS1007249432 (9:34523625 A>C,G), RS1008326448 (9:34522020 C>G,T), RS1008909924 (9:34522019 C>A), RS1009425739 (9:34524586 G>A)

Disease associations

OMIM: gene MIM:618556 | 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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	3
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
butyraldehyde	increases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Camptothecin	increases expression	1
Cocaine	decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Heroin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases expression	1

Clinical trials (associated diseases)

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