Liver Gene Expression Signature in Human NAFLD: NASH but not Simple Steatosis May be associated with increased Cardiovascular Risk by Overexpression of Angiotensin I Converting Enzyme, Transforming Growth Factor1 and Selectin L

SOOKOIAN S; FERNADEZ GIANNOTTI T; ROSSELLI MS; BURGUEÑO A,; CASTANO GO; PIROLA CJ

Boston, MA, USA

Congreso; AASLD: The Liver Meeting 2010-AASLD's 61st Annual Meeting; 2010

American Association for the Study of Liver Diseases

Epidemiological studies suggested a possible role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease. We postulate that the inflamed liver is not a bystander comorbidity but plays a key role in the development of the proatherogenic state associated with the Metabolic Syndrome phenotype. To address this hypothesis we evaluated the liver mRNA gene expression signature of 84 atherosclerosis-related genes in patients with NAFLD proven through biopsy in a case-control design. Control liver specimens were obtained by percutaneous liver biopsy. Our second goal was to evaluate the differential gene expression in fatty liver without inflammation (simple steatosis-SE) and nonalcoholic steatohepatitis (NASH). Gene expression was evaluated by quantitative RT-PCR analysis; data is expressed as fold-change calculations. Results: NASH significantly increases the expression of TGFB1 (3.8, p<0.008) and decreases PPARG (-3.2, p<0.006), when compared with normal liver. When compared with SE, NASH increases the abundance of 10 genes: 4 genes associated with atherosclerotic risk, such as ACE (2.1, p<0.007), selectin L (2.1, p<0.007), SERPINB2 (2.1, p<0.007) and TGFB1 (6.8, p<0.005), 4 genes involved in inflammation and cytokine signaling, such as colony stimulating factor 2-CSF2 (2.5, p<0.002), IL1A (2.5, p<0.005), IL3 (2.1, p<0.007) and IL4 (2.1, p<0.007), 1 gene involved in cell proliferation/growth: leukemia inhibitory factor-LIF (2.1, p<0.007), and 1 gene involved in extracellular matrix remodeling: MMP1 (2.1, p<0.007). Among the genes which their mRNA expression were down-regulated in NASH vs. SE, the most significant ones were 4 genes involved in the signaling cascade of TNFa-induced necrotic cell death, such as: TNFa-induced protein 3-TNFAIP3 (-13.7, p<0.000002), NFkB (-15.3, p< 0.00002), CFLAR (-10.4, p<0.001) and FAS (-16.5, p<0.008). An interesting gene that is activated by severe hypoxia, BIRC3, was the only one significantly increased in SE when compared with controls (8.2, p<0.004). In conclusion: NASH but not SE may increase the atherosclerotic and cardiovascular risk by local overexpression of adhesion molecules (selectin L), mediators of atherogenesis and endothelial damage (TGFB1), and regulators of blood pressure and systemic vascular resistance (ACE); this observation may have therapeutic implications. TGFB1 appears to be a molecular mediator in the pathophysiology of NAFLD: its overexpression may explain not only the nature of the fibrosis process but also the liver-apoptotic pathway triggered in NAFLD. Finally, hepatocyte hypoxia seems to have an important role in the molecular events activated by liver steatosis.