Contribution of extracellular vesicles to steatosis-related liver disease and their therapeutic potential

Table 2 Extracellular vesicle proteome in liver disease

Disease	Protein	Gene name and alias symbols	Role in liver disease	Vesicle source	Expression in disease
NAFLD	Apolipoprotein C-III	Apolipoprotein C3	An increased expression leads to increased steatosis in NAFLD[53]	EVs from human serum[53]	↑ NAFLD patients[53]
	Composition: 79 AA	APOC3
	MW: 10.85 kDa	Apo-CIII
	UA: P02656	ApoC-III
	HGNC ID: 610	APOCIII
	Cytogenetic band: 11q23.3	Apo-C3
		ApoC-3
	Apolipoprotein C-I	Apolipoprotein C1	An increased expression leads to increased steatosis in NAFLD[53]	EVs from human serum[53]	↑ NAFLD patients[53]
	Composition: 83 AA	APOC1
	MW: 9.33 kDa
	UA: P02654
	HGNC ID: 607
	Cytogenetic band: 19q13.32
	Retinol-binding protein 4	Retinol binding	Enhances the M1-like polarization of Kupffer cells via promoting the activation of NOX2 and NF-κB and ROS accumulation[72]	Serum exosomes from NAFLD patients[72]	↑ NAFLD patients[72]
	Composition: 201 AA	protein 4
	MW: 23.01 kDa
	UA: P02753	RBP4b
	HGNC ID: 9922
	Cytogenetic band: 10q23.33
	Receptor-type tyrosine-protein phosphatase gamma	Protein tyrosine phosphatase receptor type G	Hepatic PTPRG mRNA increase proportionally to the severity of NAFLD[55]	Exosomes from human plasma and murine plasma, serum, and tissue[73]	↑ of plasmatic approximately 120 kDa protein isoform were associated with the occurrence of liver damage[73]
					↑ NASH[55]
	Composition: 1445 AA	PTPRG
	MW: 162.03 kDa	RPTPG
	UA: P23470
	HGNC ID: 9671
	Cytogenetic band: 3p14.2
	C-X-C motif chemokine 10	C-X-C motif chemokine ligand 10	Lipotoxic hepatocyte-derived EVs containing CXCL10 induce macrophage chemotaxis[74,75]	EVs from Mlk3-/- mice[74,75]	↑ NASH model[74,75]
	Composition: 98 AA
	MW: 10.88 kDa	CXCL10
	UA: P02778	IFI10
	HGNC ID: 10637	IP-10
	Cytogenetic band: 4q21.1	crg-2
		mob-1
		C7
		gIP-10
	Fibulin-1	Fibulin-1	Correlate with fibrosis stage[54]	EVs from human serum[54]	↑ NAFLD patients[54]
	Composition: 703 AA
	MW: 77,214 kDa	FBLN1
	UA: P23142	FBLN
	HGNC ID: 3600
	Cytogenetic band: 22q13.31
	Fibulin-3	EGF containing fibulin extracellular matrix protein 1	Increase with liver fibrosis. Predictor of liver-related events[54]	EVs from human serum[54]	↑ NAFLD patients[54]
	Composition: 493 AA
	MW: 54.64	EFEMP1
	UA: Q12805	S1-5
	HGNC ID: 3218	FBLN3
	Cytogenetic band: 2p16.1	MTLV
NASH	Antithrombin-III	Serpin family C member 1	Almost all of the downregulated proteins are produced in the liver[57]	Exosomes from HCC human serum samples[57]	↑ ATIII in liver cirrhosis and HCC[57]
	Composition: 464 AA
	MW: 52.6 kDa	SERPINC1
	UA: P01008	ATIII
	HGNC ID: 775	MGC22579
	Cytogenetic band: 1q25.1
	Von Willebrand factor	Von Willebrand factor	Biomarker of severe liver fibrosis diagnosis and HCC development predictor[76]	Exosomal, from serum samples[57]	↑ HCC[57]
	Composition: 2813 AA
	MW: 309.26 kDa	VWF
	UA: P04275
	HGNC ID: 12726
	Cytogenetic band: 12p13.31
	Hemopexin	Hemopexin	↓ HPX protein develops inflammation and oxidative stress in the liver[77]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 462 AA
	MW: 51.67 kDa	HPX
	UA: P02790
	HGNC ID: 5171
	Cytogenetic band: 11p15.4
	Galectin 3 binding protein	Galectin 3 binding protein	Significant biomarker in liver fibrosis, cirrhosis, and HCC in patients with hepatitis C[78]	Exosomes from serum samples[57]	↑ HCC[57]
	Composition: 585 AA
	MW: 65.33 kDa.	LGALS3BP
	UA: Q08380	MAC-2-BP
	HGNC ID: 6564	90K
	Cytogenetic band: 17q25	BTBD17B
		ANGO10B
		M2BP
		gp90
		CyCAP
Cirrhosis	Transforming growth factor beta 1	Transforming growth factor beta 1	Promotes HSC activation and ECM production, contributing NAFLD progression[79,80]	Exosomal, from serum samples[57]	↑ HCC[57]
	Composition: 390 AA			Hepatoma cell lines, culture media[81]	↑ Promote tumor metastasis[81]
	MW: 44.32 kDa	TGFB1		Ascites derived exosomes, from hepatic cirrhosis patients[82]	↑ Promote cancer[82]
	UA: P01137	CED
	HGNC ID: 11766	TGFbeta
	Cytogenetic band: 19q13.2
	Fibulin-4	EGF containing fibulin extracellular matrix protein 2	Increased levels in cirrhosis, correlated with progression of fibrosis[56]	EVs from serum samples of patients with cirrhosis[56]	↑ Cirrhosis[56]
	Composition: 443 AA
	MW: 49.4 kDa	EFEMP2
	UA: O95967
	HGNC ID: 3219
	Cytogenetic band: 11q13.1
HCC	Haptoglobin	Haptoglobin	Patients with NAFLD with the Hp2-2 genotype had higher BMI, total cholesterol, and ferritin[83]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 406AA
	MW: 45.20 kDa	HP
	UA: P00738
	HGNC ID: 5141
	Cytogenetic band: 16q22.2
	Hemoglobin subunit alpha	Hemoglobin subunit alpha 1	Hemoglobin overexpression suppresses oxidative stress[57,84]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 142 AA			Liver biopsies from NASH patients[84]	↑ NASH[84]
	MW: 15.258 kDa	HBA1
	UA: P69905	HBA-T3
	HGNC ID: 4823
	Cytogenetic band: 16p13.3
	Fibrinogen alpha chain	Fibrinogen alpha chain	α chain fragments rapid alteration in early stages in liver fibrosis[85,86]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 866 AA,
	MW: 94.97 kDa	FGA
	UA: P02671
	HGNC ID: 3661
	Cytogenetic band: 4q31.3
	Fibrinogen gamma chain	Fibrinogen gamma chain	Rare cases of hypofibrinogenemia are associated with liver disease[87]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 453 AA
	MW: 51.51 kDa	FGG
	UA: P02679
	HGNC ID: 3694
	Cytogenetic band: 4q32.1
	Fibrinogen beta chain	Fibrinogen beta chain	Rarely, hypofibrinogenemia can present with HFSD[88]	Exosomal, from serum samples[57]	↓ HCC[57]
	Composition: 491 AA
	MW: 55.928 kDa	FGB
	UA: P02675
	HGNC ID: 3662
	Cytogenetic band: 4q31.3
	Carboxypeptidase E	Carboxypeptidase E	Promotes tumor metastasis and predicts tumor recurrence in early-stage HCC[58]	Exosomes from supernatant culture and human serum[57]	↑ HCC Promote tumor metastasis[57]
	Composition: 476 AA
	MW: 53.15 kDa	CPE
	UA: P16870
	HGNC ID: 2303
	Cytogenetic band: 4q32.3
	Vesicle-associated membrane protein-associated protein A	VAMP associated protein A	Facilitates bone-tropic metastasis of HCC by promoting osteoclastogenesis[41]	Large oncosomes from liver cancer mouse model[41]	↑ HCC[41]
	Composition: 249 AA
	MW: 27.89 kDa	VAPA
	UA: Q9P0L0	hVAP-33
	HGNC ID: 12648	VAP-A
	Cytogenetic band: 18p11.22
	Basigin	Basigin (Ok blood group)	Induces angiogenesis by stimulating VEGF production and invasiveness by stimulating MMPs	Microvesicles from SMMC-7721 cell line (Hepatocellular carcinoma)[89]	↑ HCC in vitro model[89]
	Composition: 385 AA	BSG	Promotes the invasion and metastasis of human hepatoma cells by stimulating both tumor cells and peritumoral fibroblasts to produce elevated levels of MMPs[89]
	MW: 42.2 kDa	EMMPRIN
	UA: P35613	CD147
	HGNC ID: 1116	EMPRIN
	Cytogenetic band: 19p13.3

Information regarding protein name, composition, molecular weight, and Uniprot access was obtained from UniProt consortium[90]. The information regarding the HGNC ID, cytogenetic band, gene name and alias symbols was obtained from HUGO Gene Nomenclature Committee[91]. AA: Amino acids; BMI: Body mass index; CD: Cluster of differentiation; CXCL10: C-X-C motif chemokine ligand 10; ECM: Extracellular matrix; EVs: Extracellular vesicles; HCC: Hepatocellular carcinoma; HFSD: High-fat style diet; HGNC: HUGO Gene Nomenclature Committee; HPX: Hemopexin; HSC: Hepatic stellate cells; kDa: Kilodaltons; Mlk3: Mixed-lineage protein kinase 3; MMPs: Metalloproteinases; mRNA: Messenger RNA; MW: Molecular weight; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PTPRG: Protein tyrosine phosphatase receptor type G; ROS: Reactive oxygen species; SERPINC1: Serpin family C member 1; UA: Uniprot access; VEGF: Vascular endothelial growth factor.