Liver transcriptional profile of atherosclerosis-related genes in human

SILVIA SOOKOIAN; TOMAS FERNÁNDEZ GIANOTTI; MARIA SOLEDAD ROSSELLI; ADRIANA L. BURGUEÑO; GUSTAVO O. CASTAÑO; CARLOS J. PIROLA

ATHEROSCLEROSIS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2011 vol. 218 p. 378 - 385

0021-9150

Objectives and design: Epidemiological studies have suggested a role of nonalcoholic fatty liver disease(NAFLD) in the development of cardiovascular disease. We evaluated liver mRNA expression of 84 genesencoding proteins involved in the atherosclerosis pathway in patients with NAFLD proven throughbiopsy in a case-control design, and examined the putative role of the histological disease severity inthe molecular events associated with the atherogenic profile.Results: Nonalcoholic steatohepatitis (NASH), when compared with simple steatosis (SS), significantlyincreases the expression of TGFB1 (6.8, p < 0.005), angiotensin I-converting enzyme (ACE) (2.1, p < 0.007),LAMA1 (2.1, p < 0.007), SERPINB2 (2.1, p < 0.007), CSF2 (2.5, p < 0.002), IL1A (2.5, p < 0.005), IL3 (2.1,p < 0.007), IL4 (2.1, p < 0.007), LIF (2.1, p < 0.007), and MMP1 (2.1, p < 0.007), and decreases the transcriptlevels of genes involved in the negative regulation of cell-death pathways. A post hoc analysis of liverbiopsies of NASH patients who were treated with enalapril monotherapy because of arterial hypertensionshowed a significant association with lower fibrosis scores in comparison with untreated patients.BIRC3, a severe hypoxia-activated gene, was significantly increased in SS (8.2, p < 0.004), when comparedwith the controls. NASH, but not SS, was also associated with a significant increase in platelet abundanceof TGFB1 mRNA. Systems biology analysis revealed highly scored pathways involved in the regulation ofprogrammed cell death, angiogenesis, and immune system, in which TGFB1 was mostly involved.Conclusion: NASH, but not SS,mayincrease atherosclerotic and cardiovascular risk by local overexpressionof mediators of atherogenesis, endothelial damage, and regulators of blood pressure; this observationmayhave therapeutic implications, because ACE inhibitors may improve both cardiovascular outcomes andliver fibrosis. Hepatocyte hypoxia seems to have an important role in the molecular events activated byliver steatosis.