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Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

ABSTRACT: The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profiling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identification of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of NAFLD.

SUBMITTER: Gorden DL

PROVIDER: S-EPMC4340319 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

Gorden D Lee DL Myers David S DS Ivanova Pavlina T PT Fahy Eoin E Maurya Mano R MR Gupta Shakti S Min Jun J Spann Nathanael J NJ McDonald Jeffrey G JG Kelly Samuel L SL Duan Jingjing J Sullards M Cameron MC Leiker Thomas J TJ Barkley Robert M RM Quehenberger Oswald O Armando Aaron M AM Milne Stephen B SB Mathews Thomas P TP Armstrong Michelle D MD Li Chijun C Melvin Willie V WV Clements Ronald H RH Washington M Kay MK Mendonsa Alisha M AM Witztum Joseph L JL Guan Ziqiang Z Glass Christopher K CK Murphy Robert C RC Dennis Edward A EA Merrill Alfred H AH Russell David W DW Subramaniam Shankar S Brown H Alex HA

Journal of lipid research 20150117 3

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strate ...[more]

PMID: 25598080

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Project description:Background & aimsIn experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication.MethodsWe studied 39 participants with 3 distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 min. Hepatic and systemic venous blood was sampled simultaneously at 3 time points: baseline, 60, and 180 min after alcohol intervention. Liver biopsies were sampled 240 min after alcohol intervention. We used ultra-high performance liquid chromatography mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples.ResultsAfter alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased, while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, whereas LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared with systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD.ConclusionsAlcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD.Clinical trials registrationThe study is registered at Clinicaltrials.gov (NCT03018990).Lay summaryWe report that alcohol induces hepatic extraction of free unsaturated fatty acids and lysophosphatidylcholines, hepatotoxic lipids which have not been previously associated with alcohol-induced liver injury. We also found that individuals with non-alcoholic fatty liver disease have reduced lipid turnover during alcohol intoxication when compared with people with alcohol-related fatty liver disease. This may explain why alcohol is particularly more harmful in people with non-alcoholic fatty liver and why elevated BMI and alcohol have a synergistic effect on the risk of liver-related death.

Dataset Information

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

Publications

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

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