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

Abstract

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 (1)H NMR spectroscopy of urine, liver and serum. Male Sprague-Dawley rats were subjected to either surgical removal of approximately 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 (1)H 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.

Integrated Histopathological and Urinary Metabonomic Investigation of the Pathogenesis of Microcystin-LR Toxicosis

“…A time-dependent shift in metabolite increase from guanidinoacetate to creatine and from betaine to dimethylglycine was observed. 5 Similar changes were observed in our study after microcystin-LR treatment, which could support the interpretation that these markers highlight the onset of tissue repair.…”

“…Reductions in TCA cycle intermediates are believed to be nonspecific biochemical changes, due in part to an elevated energy demand and/or a reduced food intake, rather than relating to tissue-specific toxicity. 5 In rats that were food restricted, citrate and 2-oxoglutarate were depleted after 24 hours of 50%, 75%, and 100% food depletion (unpublished data). However, previous studies of hydrazine toxicity in pair-fed male rats where animals were weight matched resulted in alterations in the levels of citrate, 2-oxoglutarate, hippurate, and creatinine in control rats where food had been restricted, 10 indicating that the changes in these metabolites are not due exclusively to food restriction.…”

“…3,8 Recently, the changes in 1-carbon metabolites guanidinoacetate, creatine, betaine, and dimethylglycine were discussed in a model of tissue regeneration. 5 In that study, partial hepatectomy was performed and metabolites were monitored over the course of 168 hours post treatment. A time-dependent shift in metabolite increase from guanidinoacetate to creatine and from betaine to dimethylglycine was observed.…”

Method for liver tissue metabolic profiling study and its application in type 2 diabetic rats based on ultra performance liquid chromatography–mass spectrometry

“…It is suitable for the analysis of in vivo tissue without scathe [11][12][13][14]. Besides, various liver metabolic profiling determinations were carried out by gas chromatography/mass spectrometry (GC/MS) in current research.…”

NMR metabolic profiling of the liver following administrationof alcohol andthemushroom Ganoderma lucidum in rats

“…Уменьшение холина может свидетельствовать о повышенном запросе на него в организме при актив-ном клеточном делении (Bollard et al, 2010), что хорошо согласуется с отрицательной корреляцией между уров-нем холина в печени и числом двуядерных гепатоцитов в группах крыс, получавших алкоголь (r = -0,61, p < 0,05) и алкоголь в сочетании с Рейши (r = -0,59, p < 0,05).…”