Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

Table 1 Proteomic studies of non-alcoholic fatty liver disease

Protein categories	Protein markers	Ref.	Year	Findings	Implications
Protein carrier	Apolipoproteins	Choe et al[21]	2013	Independent association between ApoB/ApoA1 ratio and NAFLD	NAFLD is the hepatic manifestation of MetSApoB/ApoA1 ratio as a predictable marker of cardiovascular risk in NAFLD
	CD5L	Gray et al[22]	2009	Identified a pattern of serum apolipoproteins and CD5L to distinguish between pre-cirrhotic NAFLD and cirrhotic NAFLD	Possibility of different trigger factors for the progression of NAFLD, NASH to HCC
Metabolic pathways	CPS1	Rodríguez-Suárez et al[24]	2010	Identified CD5L as poor biomarkers for HCCDecreased in NASH compared to control patients	Down-regulation of CPS1 may lead to an increase of uric acid[31]
	GRP78	Rodríguez-Suárez et al[24]	2010	Decreased in NASH compared to control patients	Increased de novo lipogenesis might play a role in NAFLD pathogenesis[27]
	Uric Acid	Sirota et al[33]	2013	Association of increased serum uric acid level and severity of NAFLD	Mitochondrial oxidative damage could contribute to hepatic steatosis
Acute phase protein	hs-CRP	Yoneda et al[39]	2007	Increased hs-CRP serum level in advanced NASH	Acute phase proteins may have an immediate role in hepatocytes injuries predictive markersSerum levels of acute phase proteins do not necessary reflect the severity of diseaseNAFLD progression has a more complex underlying protein mechanism
	Haemoglobin	Yu et al[42]	2012	Association of elevated serum haemoglobin levels and prevalence of NAFLD
	Fuc-Hpt	Kamada et al[44]	2013	Stepwise increased with increasing hepatocyte ballooning scores in biopsy-proven NAFLD patients
	PTX-3	Yoneda et al[47]	2008	A profound elevation of plasma PTX-3 level in NASH patients
Anti-inflammatory and anti-oxidant	Bilirubin	Kwak et al[49]	2012	An inverse relationship between total serum bilirubin level and the prevalence of NAFLD	Bilirubin has antioxidant, anti-inflammatory and anti-fibrogenic effects
Extracellular matrix	Hyaluronic acid	Kaneda et al[56]	2006	Association of increased serum concentration of ECM components and degree of fibrosis in NAFLD	An imbalance of ECM production and degradation could lead to fibrogenensis, but not specific to NAFLD
	Type IV collagen 7S	Yoneda et al[59]	2007
	Laminin	Gabrielli et al[60]	1996
	Lumican	Krishnan et al[64]	2012	Over-expressed of Lumican with increasing severity of NAFLD and NASH	Unregulated tissue remodelling and fibrogenesis could contribute to the progression of NAFLD
	MMP-9	D'Amico et al[72]	2010	An increase in serum MMP-9 levels in NASH and hepatitis C infected patientsDemonstrated a difference of immunolabelling patterns between NASH and hepatitis C infected liver	Possibility of a different pathophysiological involvement of protease in the fibrogenesis of different liver etiology
		Wanninger et al[67]	2011	Association of MMP-9 activity and hepatic inflammationA negative correlation of MMP-9 activity and serum adiponectin	Possibility of peripheral adipocytes involvement in NAFLD progression
Immune cells and cytokines	CCL2/MCP1	Haukeland et al[81]	2006	Demonstrated an increasing level of CCL2/MCP1, from healthy controls to NASH	The lipid accumulation from visceral tissue and hepatocellular could be responsible for the recruitment of immune cells
	RBP4	Bell et al[18]	2010	A decreased expression of RBP4 with increasing NAFLD severity	RBP4 could contribute to the fibrogenesis pathway in NAFLD
		Alkhouri et al[84]	2009	An inverse relationship between RBP4 levels and liver fibrosis
		Graham et al[87]	2006	Association of increased serum RBP4 with T2DM and a decreased expression of glucose transporter 4	RBP4 is associated with insulin resistance and T2DM
		Christou et al[88]	2012	RBP4 has the ability to induce insulin resistance in the adipose tissueCirculating RBP4 can be influenced by non-metabolic conditions and interventions	The association of RBP4 level and MetS is still not conclusive and should be interpret with caution

NAFLD: Non-alcoholic fatty liver disease; MetS: Metabolic syndrome; NASH: Non-alcoholic steatohepatitis; HCC: Hepatocellular carcinoma; CPS1: Carbamoyl phosphate synthase 1; hs-CRP: High sensitivity C-reactive protein; PTX-3: Pentraxin 3; ECM: Extracellular matrix; MMP: Matrix metalloproteinases; CCL2/MCP1: CC-chemokine ligand 2/monocyte chemo-attractant protein-1; T2DM: Type II diabetes mellitus.