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

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...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2009-03, Vol.296 (3), p.G553-G562
Main Authors: Ferré, Natàlia, Martínez-Clemente, Marcos, López-Parra, Marta, González-Périz, Ana, Horrillo, Raquel, Planagumà, Anna, Camps, Jordi, Joven, Jorge, Tres, Alba, Guardiola, Francesc, Bataller, Ramón, Arroyo, Vicente, Clària, Joan
Format: Article
Language:English
Subjects:
Animals
Apolipoproteins E - genetics
Biochemistry
Carbon Tetrachloride - toxicity
Chemical and Drug Induced Liver Injury
Chemokine CCL2 - metabolism
Cholesterol
Cholesterol - metabolism
Genetic Predisposition to Disease
Hepatic Stellate Cells - metabolism
Hepatic Stellate Cells - secretion
Hydroxycholesterols - metabolism
Hypercholesterolemia - genetics
Hypercholesterolemia - metabolism
Interleukin-8 - secretion
Liver
Liver diseases
Liver Diseases - genetics
Liver Diseases - metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
NF-kappa B - metabolism
Oxidation
Oxidative Stress - physiology
Proteins
Rodents
Superoxide Dismutase - metabolism
Transforming Growth Factor beta1 - secretion
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Summary: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-beta1, 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 alpha-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-kappaB-independent mechanism and upregulated TIMP-1 expression. In macrophages, oxysterols increased TGF-beta1 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.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00547.2007