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Increased susceptibility to exacerbated liver injury in hypercholesterolemic ApoE-deficient mice: potential involvement of oxysterols

¹Department of Biochemistry and Molecular Genetics, ²Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red: Enfermedades Hepáticas y Digestivas, Universitat de Barcelona, Barcelona, Spain; ³Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan de Reus, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain; ⁴Nutrition and Food Science Department-Xarxa de Referencia en Tecnologia dels Aliments-Institut de Recerca en Nutrició i Seguretat Alimentària, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

Submitted 23 November 2007 ; accepted in final form 22 December 2008

The contribution of metabolic factors to the severity of liver disease is not completely understood. In this study, apolipoprotein E-deficient (ApoE^–/–) mice were evaluated to define potential effects of hypercholesterolemia on the severity of carbon tetrachloride (CCl₄)-induced liver injury. Under baseline conditions, hypercholesterolemic ApoE^–/– mice showed increased hepatic oxidative stress (SOD activity/4-hydroxy-2-nonenal immunostaining) and higher hepatic TGF-β₁, MCP-1, and TIMP-1 expression than wild-type control mice. After CCl₄ challenge, ApoE^–/– mice exhibited exacerbated steatosis (Oil Red O staining), necroinflammation (hematoxylin-eosin staining), macrophage infiltration (F4/80 immunohistochemistry), and fibrosis (Sirius red staining and -smooth muscle actin immunohistochemistry) and more severe liver injury [alanine aminotransferase (ALT) and aspartate aminotransferase] than wild-type controls. Direct correlations were identified between serum cholesterol and hepatic steatosis, fibrosis, and ALT levels. These changes did not reflect the usual progression of the disease in ApoE^–/– mice, since exacerbated liver injury was not present in untreated age-paired ApoE^–/– mice. Moreover, hepatic cytochrome P-450 expression was unchanged in ApoE^–/– mice. To explore potential mechanisms, cell types relevant to liver pathophysiology were exposed to selected cholesterol-oxidized products. Incubation of hepatocytes with a mixture of oxysterols representative of those detected by GC-MS in livers from ApoE^–/– mice resulted in a concentration-dependent increase in total lipoperoxides and SOD activity. In hepatic stellate cells, oxysterols increased IL-8 secretion through a NF-B-independent mechanism and upregulated TIMP-1 expression. In macrophages, oxysterols increased TGF-β₁ secretion and MCP-1 expression in a concentration-dependent manner. Oxysterols did not compromise cell viability. Taken together, these findings demonstrate that hypercholesterolemic mice are sensitized to liver injury and that cholesterol-derived products (i.e., oxysterols) are able to induce proinflammatory and profibrogenic mechanisms in liver cells.

hypercholesterolemia; liver cells; cholesterol-oxidized products; apolipoprotein E