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

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.

Metalloproteinases in liver fibrosis: current insights

“…23 Upon this diet, steatosis develops not only in pericentral zones but also in periportal zones, which are specialized in gluconeogenesis. 26 In the NASH studies, a diet deprived of methionine and choline (MCD diet), which are needed for beta-oxidation, is used. Rodents fed with MCD develop pericentral fibrosis with necrosis.…”

Characterization of hepatocyte-based in vitro systems for reliable toxicity testing

“…Valproic acid mainly triggers microvesicular steatosis by impairment of mitochondrial beta oxidation and inhibition of carnitine palmitoyl transferase 1. Of note, valproic acid undergoes bio-activation, supported in part by cytochrome P450 2C9, to a metabolite that is more steatogenic and cytotoxic compared to the parent drug (Willebrords et al 2015). As for acetaminophen, valproic acid-related toxicity therefore necessitates high biotransformation capacity of the hepatocyte-based in vitro system.…”

<b>Participação da conexina 32 na fisiopatogênese da doença hepática gordurosa não alcoólica em camundongos</b>

“…Diversosmodelos experimentais vêm sendo utilizados para estudar os mecanismos fisiopatogênicos da DHGNA, assim como novas propostas diagnósticas e terapêuticas (WILLEBRORDS et al, 2015). Os roedores são os animais mais utilizados para experimentos relacionados com esteatose hepática, porém nos últimos anos, estudos feitos com zebrafish têm sido bastante utilizados por ser de baixo custo, de fácil manipulação genética e por desenvolver rapidamente doenças hepáticas (KIM et al, 2015;WILLEBRORDS et al, 2015).…”

“…Os roedores são os animais mais utilizados para experimentos relacionados com esteatose hepática, porém nos últimos anos, estudos feitos com zebrafish têm sido bastante utilizados por ser de baixo custo, de fácil manipulação genética e por desenvolver rapidamente doenças hepáticas (KIM et al, 2015;WILLEBRORDS et al, 2015).…”