The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease

Nikolaos Perakakis, Konstantinos Stefanakis, Christos S Mantzoros, Nikolaos Perakakis, Konstantinos Stefanakis, Christos S Mantzoros

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.

Keywords: Epigenomics; Genomics; Glycomics; Lipidomics; Metabolomics; NASH; Steatosis; Transcriptomics.

Conflict of interest statement

Declaration of competing interest C.S.M. and N.P. have applied for patent through their institution BIDMC. CSM has been a shareholder of and reports grants through his institution and personal consulting fees from Coherus Inc. and Pangea Inc., he reports grants through his institution and personal consulting fees from Esai and Novo Nordisk, reports personal consulting fees and in kind support with research reagents from Ansh inc, reports personal consulting fees from Genfit, P.E.S., Intercept, Astra Zeneca, Aegerion and Regeneron, reports in kind support (educational activity meals at and through his institution) from Amarin, Jansen, Boehringer Ingelheim and travel support and fees from TMIOA, the California Walnut Commission, College Internationale Researche Servier and the Cardio Metabolic Health Conference.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Main omics procedures used currently in medicine and in NAFLD research.
Fig. 2
Fig. 2
Genomic, epigenomic and transcriptomic modifications in NAFLD pathophysiology. PNPLA3, TM6SF2 and GCKR are some of the most investigated genes in NAFLD. Adiponutrin (PNPLA3) variant I148M (rs738409) impairs PUFA transfer from DAGs to PCs, thus increasing PUFA in TG and DAG. TM6SF2 E167K (rs58542926) impairs PUFA synthesis, increases polyunsaturated FFAs and prevents PUFA incorporation into TGs and PCs. Both mechanisms lead to impaired VLDL synthesis and lipid droplet hydrolysis. GCKR P446L (rs780094) incites glycolysis, glycogen deposition and de novo lipogenesis by disinhibiting glucokinase. Epigenetic modifications characteristic of NAFLD progression include CpG site hypermethylation, thus reduced expression, of genes pertaining to lipid and aminoacid metabolism and stellate cell inhibition. Hypomethylation, thus increased expression, of genes pertaining to tissue repair, inflammation, carcinogenesis and fibrogenesis, increases insulin resistance and further propagates the disease. Methylation levels of cytoskeletal, transcriptional, proliferation-related and metabolic genes are affected by age, fasting glucose levels and body weight. At the histone level, depletion of sirtuins 1 and 3 and HDAC3 may propagate NASH and increase susceptibility to MetS, insulin resistance and hyperlipidemia. On the other hand, the glucose-activated HAT p300 activates ChREBP and thus precipitates stellate cell activation, elevates lipogenic gene expression and expedites steatosis, though these effects can be attenuated by tannic acid. Finally, the NAFLD transcriptome is characterized by overexpression of lipid metabolism, cellular stress, division and adhesion, extracellular matrix production and repair, cancer progression and immunomodulatory genes, whereas several pro-metabolic and insulin signaling genes are downregulated. miRNAs, especially miR-122, miR-192 and miR-34a, are linked to steatosis, cholesterol metabolism, liver cancer, atherogenesis and MetS, whereas other noncoding molecules, such as lncRNAs, are indicators of NASH grade and hepatocellular viability.
Fig. 3
Fig. 3
Perturbations in lipidomic profile related to the pathophysiology of NAFLD. The uncontrolled lipolysis from adipose tissue, the increased dietary intake of TG and the upregulated de novo lipogenesis observed in NAFLD leads to elevated SFA, LPC, Ceramides and ω6/ω3 PUFA ratio. SFA stimulate the secretion of inflammatory cytokines via TLR4 and apoptosis via TRAIL2, whereas they increase oxidative stress, ER stress and impair β-oxidation in the mitochondria of hepatocytes. In stellate cells, they stimulate macrophage recruitment, whereas in Kupffer cells and macrophages SFA induce their polarization to the M1 proinflammatory state. Increased activation of PLA2 enzyme leads to formation of LPC and depletion of PC. PC are important for lipid droplet stability and their deficiency leads to large droplet formation and inadequate VLDL secretion. High LPC are also triggering mechanisms of impaired β-oxidation, apoptosis, fibrosis and HCC. High hepatic ceramide concentrations increase cholesterol synthesis and TG accumulation, promote insulin resistance by blocking Akt-mediated insulin signaling, induce the secretion of proinflammatory cytokines and stimulate apoptosis by increasing ROS generation, ER stress and β-oxidation impairment. In hepatic stellate cells, they increase extracellular matrix deposition and pro-angiogenic factors secretion promoting fibrogenesis. Finally, the high ω6/ω3 ratio leads to increased synthesis of proinflammatory molecules, such as prostaglandins, leukotrienes, thromboxanes in expense of the synthesis of anti-inflammatory SPMs, thus resulting in a pro-inflammatory and profibrotic net outcome.

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