NMR-Based Metabolic Profiling Identifies Biomarkers of Liver Regeneration Following Partial Hepatectomy in the Rat

• Published in: Journal of proteome research Vol. 9; no. 1; pp. 59 - 69
• Main Authors: Bollard, Mary E, Contel, Nancy R, Ebbels, Timothy M. D, Smith, Leon, Beckonert, Olaf, Cantor, Glenn H, Lehman-McKeeman, Lois, Holmes, Elaine C, Lindon, John C, Nicholson, Jeremy K, Keun, Hector C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.01.2010
• Subjects: Animals; Biomarkers - analysis; Blood Chemical Analysis; Body Weight; Hepatectomy; Histocytochemistry; Liver - chemistry; Liver - metabolism; Liver - physiology; Liver - surgery; Liver Regeneration - physiology; Male; Metabolomics - methods; Nuclear Magnetic Resonance, Biomolecular - methods; Organ Size; Rats; Rats, Sprague-Dawley; Urine - chemistry; toxicity; metabonomics; 1-carbon metabolism; fatty liver; metabolomics; liver regeneration
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/pr900200v

Tissue injury and repair are often overlapping consequences of disease or toxic exposure, but are not often considered as distinct processes in molecular studies. To establish the systemic metabolic response to liver regeneration, the partial hepatectomy (PH) model has been studied in the rat by an integrated metabonomics strategy, utilizing 1H NMR spectroscopy of urine, liver and serum. Male Sprague−Dawley rats were subjected to either surgical removal of ∼two-thirds of the liver, sham operated (SO) surgery, or no treatment (n = 10/group) and samples collected over a 7 day period. A number of urinary metabolic perturbations were observed in PH rats compared with SO and control animals, including elevated levels of taurine, hypotaurine, creatine, guanidinoacetic acid, betaine, dimethylglycine and bile acids. Serum betaine and creatine were also elevated after PH, while levels of triglyceride were reduced. In the liver, triglycerides, cholesterol, alanine and betaine were elevated after PH, while choline and its derivatives were reduced. Upon examining the dynamic pattern of urinary response (the ‘metabolic trajectory’), several metabolites could be categorized into groups likely to reflect perturbations to different processes such as dietary intake or hepatic 1-carbon metabolism. Several of the urinary perturbations observed during the regenerative phase of the PH model have also been observed after exposure to liver toxins, indicating that hepatic regeneration may make a contribution to the systemic alterations in metabolism associated with hepatotoxicity. The observed changes in 1-carbon and lipid metabolism are consistent with the proposed role of these pathways in the activation of a regenerative response and provide further evidence regarding the utility of urinary NMR profiles in the detection of liver-specific pathology. Biofluid 1H NMR-based metabolic profiling provides new insight into the role of metabolism of liver regeneration, and suggests putative biomarkers for the noninvasive monitoring of the regeneration process.