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.

Table 2 Genomic studies of non-alcoholic fatty liver disease

Gene categories	Genes	Ref.	Year	Findings	Implications
Gene that affect lipolysis	PNPLA3	Romeo et al[91]	2008	PNPLA3 polymorphism is strongly associated with the pathogenic status of NAFLD in different populations	A well established link between PNPLA3 and NAFLD progression
		Sookoian et al[94]	2011	GG genotype of PNPLA3 (rs738409; I148M) exerts a stronger effect on hepatic lipids accumulations	Identified the patients group who is more susceptible to aggressive diseases
		Dubuquoy et al[95]	2013	PNPLA3 polymorphism is more likely to influence lipid content and liver disease severity but not insulin resistance	A less clear association of insulin resistance with PNPLA3 polymorphism
	ATGL	Chitraju et al[102]	2013	Demonstrated that ATGL-KO animal models have high insulin sensitivity	An accumulation of TG could be a protective mechanism in NAFLD
	ApoC3	Petersen et al[106]	2010	ApoC3 polymorphism is associated with NAFLD and insulin resistance in Indian populations	Highlighted the ethnic differences in ApoC3 polymorphism and disease susceptibility
		Hyysalo et al[107]	2012	ApoC3 polymorphism does not associated with NAFLD in Finnish populations
	GCKR	Santora et al[108]	2012	GCKR polymorphism is associated with NAFLD	Lipogenesis pathway plays a role in NAFLD pathogenesis
		Tan et al[112]	2013	Interactions of GCKR and PNPLA3 genes can increase susceptibility to NAFLD
	PPARGC1A and PPAR-γ	Hui et al[116]	2008	PPARGC1A gene polymorphism is not associated with NAFLDPPAR-α is associated with NAFLD susceptibility	The PGC-1α and PPAR-γ pathway play a role in NAFLD progression The role of PCG-1α (encoded by the PPARGC1A gene) in MetS is less clear than PPAR-γ
		Gawrieh et al[119]	2012	PPAR-γ polymorphism is associated with NAFLD
Genes that affect adipokines	Adiponectin	Musso et al[126]	2008	Adiponectin gene polymorphism is associated with the presence of NAFLD	De novo lipogenesis plays a role in NAFLD
		Han et al[130]	2011	Adiponectin gene polymorphism does not influence the development of T2DM	Possibility of different mechanisms for insulin sensitising in NAFLD
		Li[20]	2012
		Muhidin et al[134]	2012	Demonstrated a correlation between NAFLD and colorectal cancer	Raises the possibility and association of anti-inflammatory effect in NAFLD progression and oncological disease
	LEP and LEPR	Zain et al[139]	2013	Demonstrated an association between variants of LEPR and PNPLA3	Patients with mutations of both LEPR and PNPLA3 are highly susceptible to NAFLD
Genes that affect cytokines	TNF-α	Wang et al[142]	2012	Polymophisms of TNF-α are associated with the susceptibility to NAFLD	Insulin resistance and hepatic inflammation are relatedInsulin signal transduction pathway does contribute to the progression of NAFLD
	IL-6	Carulli et al[146]	2009	Polymorphisms of IL-6 are more prevalent in NAFLD and associated with insulin resistance
		Giannitrapani et al[145]	2013	Polymorphisms of IL-6 are unlikely to associate with insulin resistance

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; PPAR-γ: Peroxisome proliferator activated receptor gamma.