RESUMO
UNLABELLED: Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. CONCLUSION: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients.
Assuntos
Fígado Gorduroso/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/farmacologia , Fígado/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Linhagem Celular , Receptor Constitutivo de Androstano , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos não Esterificados/efeitos adversos , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Hepatopatia Gordurosa não Alcoólica , Ácido Oleico/efeitos adversos , Receptores Nucleares Órfãos/antagonistas & inibidores , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Oxazóis/farmacologia , Oxirredução , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Triglicerídeos/metabolismoRESUMO
Safety pharmacology studies are defined as the studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure. In consequence, these studies are an integral part of the non-clinical safety assessment of new pharmaceuticals, in association with toxicological studies. A retrospective shows the evolution of the discipline in these last years. Safety pharmacology studies are of special interest, and some drawbacks and pitfalls must be considered (i.e. invasive methods, difficulties related to GLP (good laboratory practices) requirements, choice of a strategy). In the future, some priority should be given to education, promotion of scientific activities, reinforcement of the links between pharmacologists and toxicologists and implementation of relevant guidelines.