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mTOR-Dependent Suppression of Remnant Liver Regeneration in Liver Failure After Massive Liver Resection in Rats

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Abstract

Background and Aims

Massive hepatectomy often leads to fatal liver failure because of a small remnant liver volume. The aim of this study was to investigate the potential mechanisms leading to liver failure.

Methods

Sprague–Dawley rats had performed a sham operation, 85 % partial hepatectomy (PH) or 90 % PH, and all had free access to water with or without supplemented glucose. Liver function and survival were evaluated. Liver parenchymal injury was assessed by evaluating hepatic pathology, blood biochemistry, and apoptotic and necrotic alterations. The regeneration response was assessed by the weight gain of the remnant liver, hepatocyte proliferation markers, and regeneration-related molecules.

Results

The 90 % hepatectomy resulted in a significantly lower survival rate and impaired liver function; however, no significant more serious liver parenchymal injuries were detected. TNF-α, HGF, myc and IL-6 were either similarly expressed or overexpressed; however, the increase in remnant liver weight, mitotic index, and the presence of Ki-67 and PCNA were significantly lower in the 90 %-hepatectomized rats. mTOR, p70S6K and 4EBP1 were not activated in the remnant liver after a 90 % hepatectomy as obviously as those after an 85 % hepatectomy, which was concomitant with the higher expression of phospho-AMPK and a lower intrahepatic ATP level. Glucose treatment significantly improved the survival rate of 90 %-hepatectomized rats.

Conclusions

Suppression of remnant liver regeneration was observed in the 90 % PH and contributed to fatal liver failure. This suppressed liver regenerative capacity was related to the inhibited activation of mTOR signaling.

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Acknowledgments

This work was supported by the National Key Technology R&D Program of China (No. 2012BAI06B01) and National S&T Major Project for Infectious Diseases of China (No. 2012ZX10002-017).

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None.

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Authors and Affiliations

  1. Department and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China

    Dong Xin Zhang, Chong Hui Li, Ai Qun Zhang, Yan Hua Lai, Xin Lan Ge, Ke Pan & Jia Hong Dong

  2. Department of Plastic Surgery, Chinese PLA General Hospital, Beijing, China

    Shan Jiang

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  1. Dong Xin Zhang
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  2. Chong Hui Li
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Correspondence to Jia Hong Dong.

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Zhang, D.X., Li, C.H., Zhang, A.Q. et al. mTOR-Dependent Suppression of Remnant Liver Regeneration in Liver Failure After Massive Liver Resection in Rats. Dig Dis Sci 60, 2718–2729 (2015). https://doi.org/10.1007/s10620-015-3676-y

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  • DOI: https://doi.org/10.1007/s10620-015-3676-y

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