Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance.
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abstract
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Hepatic insulin resistance and hepatosteatosis in diet-induced obesity are associated with various metabolic diseases, yet the underlying mechanisms remain to be fully elucidated. Here we show that the expression levels of the disulfide-bond A oxidoreductase-like protein (DsbA-L) are significantly reduced in the liver of obese mice and humans. Liver-specific knockout or adenovirus-mediated overexpression of DsbA-L exacerbates or alleviates, respectively, high-fat diet-induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance in mice. Mechanistically, we found that DsbA-L is localized in mitochondria and that its deficiency is associated with impairment of maximum respiratory capacity, elevated cellular oxidative stress, and increased JNK activity. Our results identify DsbA-L as a critical regulator of mitochondrial function, and its down-regulation in the liver may contribute to obesity-induced hepatosteatosis and whole body insulin resistance.-Chen, H., Bai, J., Dong, F., Fang, H., Zhang, Y., Meng, W., Liu, B., Luo, Y., Liu, M., Bai, Y., Abdul-Ghani, M. A., Li, R., Wu, J., Zeng, R., Zhou, Z., Dong, L. Q., Liu, F. Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance.© FASEB.
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keywords
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Adenosine Triphosphate
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Animals
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Diet, High-Fat
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Dietary Fats
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Fatty Liver
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Gene Expression Regulation, Enzymologic
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Glucose Clamp Technique
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Glutathione Transferase
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Hepatocytes
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Humans
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Insulin Resistance
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Liver
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Male
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Mice
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Mice, Knockout
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Mitochondria, Liver
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Oxidative Stress
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Oxygen Consumption
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