Changes in human hepatic metabolism in steatosis and cirrhosis

Abstract

AIMTo understand the underlying metabolic changes in human liver disease we have applied nuclear magnetic resonance (NMR) metabolomics analysis to human liver tissue.METHODSWe have carried out pilot study using 1H-NMR to derive metabolomic signatures from human liver from patients with steatosis, nonalcoholic steatohepatitis (NASH) or alcohol-related liver damage (ARLD) to identify species that can predict outcome and discriminate between alcohol and metabolic-induced liver injuries.RESULTSChanges in branched chain amino acid homeostasis, tricarboxylic acid cycle and purine biosynthesis intermediates along with betaine were associated with the development of cirrhosis in both ARLD and nonalcoholic fatty liver disease. Species such as propylene glycol and as yet unidentified moieties that allowed discrimination between NASH and ARLD samples were also detected using our approach.CONCLUSIONOur high throughput, non-destructive technique for multiple analyte quantification in human liver specimens has potential for identification of biomarkers with prognostic and diagnostic significance.

Succinate‐GPR‐91 receptor signalling is responsible for nonalcoholic steatohepatitis‐associated fibrosis: Effects of DHA supplementation

“…This finding indicates that there was a significant impairment in the TCA cycle due to mitochondrial damage and impaired mitophagy as a mechanism in clearance of damaged mitochondria as demonstrated in our recent study . In supporting our observation in a murine NASH model, elevated succinate levels were reported in NASH patients . At the same time, GPR‐91, a G‐protein‐coupled receptor, was up‐regulated in HSCs of HFCD‐HF/G‐fed mice, HSCs with treatment of succinate in vitro and in human NASH specimens with fibrotic progression, demonstrating a positive correlation between NASH fibrosis severity and GPR‐91 positive staining in liver biopsy specimens.…”

“…21 In supporting our observation in a murine NASH model, elevated succinate levels were reported in NASH patients. 22 At the same time, GPR-91, a G-protein-coupled receptor, was up-regulated in HSCs of HFCD-HF/G-fed mice, HSCs with treatment of succinate in vitro and in human NASH specimens with fibrotic progression, demonstrating a positive correlation between NASH fibrosis severity and GPR-91 positive staining in liver biopsy specimens. GRP-91 receptor activation elicited phosphorylation of downstream signalling molecules, such as Erk and c-Jun, and production of more extracellular matrices (Procol-I, III, TIMP) and release of fibrogenic cytokines, such as CTGF.…”

Monocarboxylate Transporter 1 (MCT1) in Liver Pathology

“…Our study revealed significantly higher lactate levels in livers obtained from patients diagnosed with alcoholic liver disease compared to healthy control livers. Those results are in keeping with the report on higher lactate levels in livers in the course of nonalcoholic steatohepatitis (NASH) and alcohol-related liver damage published by Schofield et al [11].…”

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…A UK study used 1 H NMR metabolite profiling to compare livers removed from patients with either LC associated with ALD (5) or with NASH (14) with healthy donor transplant livers (16). Cirrhotic livers had significantly increased levels of isoleucine, valine, succinate, lactate, and betaine [150]. Another NMR study was conducted on Chinese patients that included those with HCC.…”