Abstract
Aim:
To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats.
Methods:
Male SD rats were orally administered VPA (100 or 500 mg·kg−1·d−1) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS.
Results:
HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism.
Conclusion:
HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (Grants 81072695 and 91029746), the National Basic Research Program of China (“973 Program”) (Grant 2011CB505300-03), the Foundation for the Author of National Excellent Doctoral Dissertation of China (Grant 200979); the Natural Science Foundation of Jiangsu province (Grant BK2010066), and the Program for a New Century Excellent Talent in University (Grant NCET-09-0770).
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Supplemental Tables and Figures are available at the website of Acta Pharmacologica Sinica.
Supplementary information
Figure S1
Typical GC/TOFMS total ion current (TIC) chromatograms of rat serum. (DOC 771 kb)
Figure S2
Typical GC/TOFMS total ion current (TIC) chromatograms of rat urine. (DOC 895 kb)
Figure S3
Typical GC/TOFMS total ion current (TIC) chromatograms of rat bile. (DOC 331 kb)
Figure S4
Heatmap visualization of intervention effect of HFD and VAP based on the identified analytes in rat serum. (DOC 612 kb)
Figure S5
Heatmap visualization of intervention effect of HFD and VAP based on the identified analytes in rat urine. (DOC 621 kb)
Figure S6
Heatmap visualization of intervention effect of HFD and VAP based on the identified analytes in rat bile. (DOC 750 kb)
Table S1
Identified endogenous compounds from rat serum, urine and bile. (DOC 118 kb)
Table S2
Relative abundance of the identified analytes showing statistically significant differences from rat serum. (DOC 136 kb)
Table S3
Relative abundance of the identified analytes showing statistically significant differences from rat urine. (DOC 128 kb)
Table S4
Relative abundance of the identified analytes showing statistically significant differences from rat bile. (DOC 173 kb)
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Zhang, Lf., Liu, Ls., Chu, Xm. et al. Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats. Acta Pharmacol Sin 35, 363–372 (2014). https://doi.org/10.1038/aps.2013.135
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DOI: https://doi.org/10.1038/aps.2013.135
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