Rubratoxin B causes lipid accumulation in fatty mouse liver
Keiko IWASHITA, Hitoshi NAGASHIMA
2008
JSM Mycotoxins
Introduction Rubratoxin B is a potent hepatotoxic mycotoxin 1-3) produced by various Penicillium fungi 2-5) . Human rubratoxicosis was first diagnosed in 1996 3) , indicating that rubratoxin B can be a threat to human health. Our previous in vitro studies showed that rubratoxin B exerts various cytotoxicities, including induction of apoptosis 6, 7) and inhibition of cell proliferation 8) , and it also induces cytokine secretion in cultured cells [9][10][11][12] . Rubratoxin B also can cause
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... re hepatic injury in experimental animals 13) and corresponding increases in serum aminotransferase activity [14][15][16][17] . Furthermore, rubratoxin B causes body weight loss 17) , hepatomegaly 17) , fatty liver 17) , hypoglycemia 16, 17) and elevated serum interleukin-6 levels 16,17) . Fatty liver is the consequence of the accumulation of lipid (typically triglycerides) in the liver as a result of alcohol consumption, excessive calorie intake, administration of certain chemicals, and other factors, and it is one of the most common symptoms of hepatic injury. In fact, nearly 1/3 of adult men and 1/5 of adult women in Japan have this symptom. In this study, to elucidate the mechanism of lipid accumulation in the livers of rubratoxin B-treated mice, we documented the types of lipid droplets accumulated and the activities of 2 lipogenic enzymes. The potent hepatotoxic mycotoxin rubratoxin B causes fatty liver. To elucidate the lipid accumulation mechanism, we investigated the type of lipid droplets accumulated and the activities of the lipogenic enzymes glucose-6-phosphate dehydrogenase (G6PD) and fatty acid synthase in mouse livers treated for 24 h with rubratoxin B. Oil Red O staining revealed numerous microvesicular lipid droplets in the liver cells of rubratoxin B-treated mice. In addition, treatment with rubratoxin B notably induced the activity of G6PD, a crucial member of the pentose phosphate cycle, which produces and supplies NADPH for fatty acid synthesis. Unexpectedly, rubratoxin B decreased the activity of fatty acid synthase, which facilitates fatty acid chain elongation. However, because fatty acid synthase is not a key enzyme in fatty acid synthesis, its activity level in rubratoxin B-treated mice may be sufficient for lipid accumulation. Materials and Methods Chemicals and Mice Rubratoxin B, Oil Red O, acetyl-CoA, and malonyl-CoA were purchased from Sigma-Aldrich (St. Louis, MO, USA). NADP, NADPH, glucose-6-phosphate, and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Inbred 9-week-old male C3H/HeNCrj mice were purchased from Charles River Japan (Yokohama, Japan). All mice were maintained under specific-pathogen-free conditions at the National Our results show that rubratoxin B caused microvesicular hepatic steatosis and affected the activities of two lipogenic enzymes. However, further studies, including those addressing the catabolism and secretion of fatty acids, are needed to clarify the detailed mechanism of rubratoxin Bcaused fatty liver.
doi:10.2520/myco.58.83
fatcat:thnrn6wey5enrn6lchqjkgtrbq