Liquid Chromatography−Mass Spectrometry-Based Parallel Metabolic Profiling of Human and Mouse Model Serum Reveals Putative Biomarkers Associated with the Progression of Nonalcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease in most western countries. Current NAFLD diagnosis methods (e.g. liver biopsy analysis or imaging techniques) are poorly suited as tests for such a prevalent condition, from both a clinical and financial point of view. The present work aims to demonstrate the potential utility of serum NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript metabolic profiling in defining phenotypic biomarkers that could be useful in NAFLD management. A parallel animal model / human NAFLD exploratory metabolomics approach was employed, using ultra performance liquid chromatography-mass spectrometry (UPLC ® -MS) to analyze 42 serum samples collected from non-diabetic, morbidly obese, biopsy-proven NAFLD patients, and 17 animals belonging to the glycine N-methyltransferase knockout (GNMT-KO) NAFLD mouse model. Multivariate statistical analysis of the data revealed a series of common biomarkers that were significantly altered in the NAFLD (GNMT-KO) subjects in comparison to their normal liver counterparts (WT). Many of the compounds observed could be associated with biochemical perturbations associated with liver dysfunction (e.g. reduced Creatine) and inflammation (e.g. eicosanoid signaling). This differential metabolic phenotyping approach may have a future role as a supplement for clinical decision making in NAFLD and in the adaption to more individualized treatment protocols.

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

“…GNMT deficiency in mice results in chronic hepatitis, fatty liver and HCC spontaneously (25,26,30). Recently, several putative metabolites identified in Gnmt -/-mice serum closely resemble those of NAFLD patients (31). Varela-Rey et al (32) also showed that nicotinamide administration normalized hepatic Sadenosylmethionine (SAM) and fatty acid metabolism, as well as prevented fatty liver development in Gnmt -/-mice.…”

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

“…For instance, FA analysis revealed that the profi les of nonalcoholic fatty liver and NASH are relatively similar, but that NASH and simple steatosis differ in their content of lipoxygenase-derived eicosanoids ( 13,14 ). Lipidomic analyses of human serum indicate that ether-linked phospholipids, certain neutral lipids, and FAs show suggestive differences between NASH and steatosis for some classes of patients by degree of obesity ( 15 ). Ceramides have been proposed to participate in the development and progression of NAFLD ( 16 ).…”

Lipid Metabolism in Liver Cancer

“…As a manifestation of steatosis, the lipogenesis (triacylglycerols, diacylglycerol, and phospholipids) [51][52][53] and bile acid biosynthesis (cholesterol esters, choline, and bile acids) [54,55] pathways were found to be up-regulated. The hepatic lipids were found to be rearranged and repartitioned from adipose to liver, rather than de novo lipogenesis and deposition in the liver, possibly through increased turnover of phosphatidylcholine and phosphatidylethanolamine [9].…”