Inflammatory liver steatosis caused by IL-12 and IL-18

Acute fatty degeneration in the liver is caused by various agents, such as aspirin, valproic acid, and ibuprofen, that directly inhibit mitochondrial beta-oxidation of fatty acid and oxidative phosphorylation. Endogenous molecules, such as cytokines and hormones, are also known to mediate microvesicular steatosis in liver failure. In this study, we examined how interleukin-12 (IL-12) and IL-18 cause steatosis in the liver. Administration of these cytokines in combination caused marked hepatosteatosis and weight loss in mice. There were marked increases in levels of interferon-gamma (IFN-gamma), nitrite (NO(2)/NO(3)), and fibrinogen in the circulation in these mice. On the other hand, the ATP concentration and blood flow in the liver were significantly reduced. These changes, except the production of IFN-gamma and NO, were partially inhibited by Z-VAD-fmk, a synthetic tripeptide inhibitor for NO-induced caspases. These results indicate that IL-12 and IL-18 may mediate inflammatory hepatosteatosis through impairment of the microcirculation, which leads to mitochondrial dysfunction in hepatocytes.