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J. Biol. Chem., Vol. 281, Issue 42, 31713-31719, October 20, 2006

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CuZn-SOD Deficiency Causes ApoB Degradation and Induces Hepatic Lipid Accumulation by Impaired Lipoprotein Secretion in Mice^*

Satoshi Uchiyama¹, Takahiko Shimizu^¶, and Takuji Shirasawa^¶||2

From the Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Applied Biological Chemistry, United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Tokyo 183-8509, ^||Biological Science, Graduate School of Science, Tokyo Metropolitan University, Tokyo 113-8421, and ^¶Anti-Aging Science Inc., Tokyo 100-0011, Japan

Elevated hepatic reactive oxygen species play an important role in pathogenesis of liver diseases, such as alcohol-induced liver injury, hepatitis C virus infection, and nonalcoholic steatohepatitis. In the present study, we investigated and compared the hepatic lipid metabolisms of liver-specific Sod2 (superoxide dismutase 2) knock-out (Sod2 KO), Sod1 knock-out (Sod1 KO), and Sod1/liver-specific Sod2 double knock-out mice (double KO). We observed significant increases in lipid peroxidation and triglyceride (TG) in the liver of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. We also found that high fat diet enhanced fatty changes of the liver in Sod1 KO and double KO mice but not in Sod2 KO mice. These data indicated that CuZn-SOD deficiency caused lipid accumulation in the liver. To investigate the molecular mechanism of hepatic lipid accumulation in CuZn-SOD-deficient mice, we measured TG secretion rate from liver using Triton WR1339. We found significant decrease of TG secretion in CuZn-SOD-deficient mice. Furthermore, we observed marked degradation of apolipoprotein B (apoB) in the liver and plasma of CuZn-SOD-deficient mice, indicating that degradation of apoB impairs secretion of lipoprotein from the liver. Our data suggest that oxidative stress enhances hepatic lipid accumulation by impaired lipoprotein secretion due to the degradation of apoB in liver.

Received for publication, April 10, 2006 , and in revised form, August 18, 2006.

^* This work was supported by grants from Comprehensive Research on Aging and Health, Ministry of Health, Labor, and Welfare and by grants-in-aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Research resident of the Japan Foundation for Aging and Health.

² To whom correspondence should be addressed: Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. Tel.: 81-3-3964-3241; Fax: 81-3-3579-4776; E-mail: sirasawa{at}tmig.or.jp.

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