Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research - PubMed (original) (raw)

Review

doi: 10.1016/j.plipres.2015.05.002. Epub 2015 Jun 11.

Isabel Veloso Alves Pereira 2, Michaël Maes 3, Sara Crespo Yanguas 4, Isabelle Colle 5, Bert Van Den Bossche 6, Tereza Cristina Da Silva 7, Cláudia Pinto Marques Souza de Oliveira 8, Wellington Andraus 9, Venâncio Avancini Alves 10, Bruno Cogliati 11, Mathieu Vinken 12

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Review

Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

Joost Willebrords et al. Prog Lipid Res. 2015 Jul.

Abstract

Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.

Keywords: Biomarkers; Drugs; Models; Non-alcoholic fatty liver disease; Steatosis.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. Pathogenesis of steatosis

Four pathogenic mechanisms can be responsible for the accumulation of TG-based lipid droplets, namely 1) increased uptake of FFAs from high-fat food or from adipocytes in body fat, 2) increased synthesis of FFAs in the liver from glucose or acetate by IR, 3) decreased mitochondrial β-oxidation of FFAs caused by a multitude of drugs, and 4) decreased synthesis or secretion of very low density lipoproteins, the principal route for elimination of lipids from the liver. (ATP, adenosine triphosphate; CoA, coenzyme A; FFA, free fatty acids; LDs, lipid droplets; IR, insulin resistance; TGs, triglyceride; VLDL, very low density lipoproteins).

Figure 2

Figure 2. Mechanisms of drug-induced liver steatosis

Drugs may induce liver steatosis by a plethora of mechanisms associated with mitochondrial impairment, including 1) inhibition of enzymes involved in mitochondrial FFA oxidation leading to a direct alteration in β-oxidation function, 2) direct inhibition of the mitochondrial respiratory chain reaction or alteration of oxidative phosphorylation, 3) decreased uptake of acyl-CoA due to the inhibition of carnitine palmitoyl transferase 1, 4) reduction in triglyceride excretion by inhibition of microsomal triglyceride transfer protein, 5) impaired entrance of fatty acids in mitochondria due to the inhibition of acyl-CoA synthase, 6) depletion of mitochondrial DNA, encoding for mitochondrial proteins, which leads to impairment of MRC, 7) induction of the mitochondrial permeability transition pore opening, 8) alteration of mitochondrial membrane potential. (ACS, acyl-coenzyme A synthase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT1, carnitine palmitoyl transferase 1; FAD, oxidized flavin adenine dinucleotide; FADH2, reduced flavin adenine dinucleotide; FFA, free fatty acids; IMS, intermembrane space; MRC, mitochondrial respiratory chain; MPT, mitochondrial permeability transition; MTTP, mitochondrial triglyceride transfer protein; NAD, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; TG, triglyceride; VLDL, very low density lipoproteins).

Figure 3

Figure 3. Histological patterns of liver steatosis

Hematoxylin and eosin (upper panel) and Oil Red (lower panel) stained liver slice from C57BL/6 mice fed a high-fat choline-deficient diet for 8 weeks developing mixed macrovesicular and microvesicular steatosis. Both pictures depict the accumulation of TGs in the cytosol of hepatocytes. However, in case of macrovesicular steatosis, large lipid droplets are observed, which displace the cytoplasmic content and nucleus, while in microvesicular steatosis, small lipid droplets that do not displace the nucleus are seen (MA, macrovesicular steatosis; MI, microvesicular steatosis).

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