Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder closely related to metabolic syndrome. NAFLD can progress to an inflammatory state called non-alcoholic steatohepatitis (NASH), which may result in the development of fibrosis and hepatocellular carcinoma. To develop therapeutic strategies against NAFLD, a better understanding of the molecular mechanism is needed. Current in vitro NAFLD models fail to capture the essential interactions between liver cell types and often do not reflect the pathophysiological status of patients. To overcome limitations of commonly used in vitro and in vivo models, precision-cut liver slices (PCLSs) were used in this study. PCLSs, prepared from liver tissue obtained from male Wistar rats, were cultured in supraphysiological concentrations of glucose, fructose, insulin, and palmitic acid to mimic metabolic syndrome. Accumulation of lipid droplets was visible and measurable after 24 h in PCLSs incubated with glucose, fructose, and insulin, both in the presence and absence of palmitic acid. Upregulation of acetyl-CoA carboxylase 1 and 2, and of sterol responsive element binding protein 1c, suggests increased de novo lipogenesis in PCLSs cultured under these conditions. Additionally, carnitine palmitoyltransferase 1 expression was reduced, which indicates impaired fatty acid transport and disrupted mitochondrial β-oxidation. Thus, steatosis was successfully induced in PCLSs with modified culture medium. This novel ex vivo NAFLD model could be used to investigate the multicellular and molecular mechanisms that drive NAFLD development and progression, and to study potential anti-steatotic drugs.
Highlights
Non-alcoholic fatty liver disease (NAFLD), known as hepatic steatosis, is a condition in which there is an abnormally high lipid deposition in the liver that is unrelated to excessive alcohol intake [1,2]
Increased carnitine palmitoyltransferase 2 (CPT2) levels have previously been linked to stress, which could be the case in precision-cut liver slices (PCLSs) [59]. These results indicate that both increased lipid synthesis and reduced lipid breakdown are connected to the steatosis in this PCLS model, which is in line with in vivo studies [22]
Microvesicular steatosis was induced in precision-cut liver slices by mimicking the NAFLD risk factors
Summary
Non-alcoholic fatty liver disease (NAFLD), known as hepatic steatosis, is a condition in which there is an abnormally high lipid deposition in the liver that is unrelated to excessive alcohol intake [1,2]. SREB-1c and MLXIPL induce acetyl-CoA carboxylase 1 (ACC1), which is involved in the synthesis of malonyl-CoA—a substrate for fatty acid synthesis and inhibitor of fatty acid oxidation. This chain of reactions results in a misbalance of carbohydrate and lipid metabolism [10,11,12], and instead of oxidizing lipids, triglyceride esterification and de novo lipogenesis (DNL) is increased [13]. Diabetes mellitus is a major co-morbid disease in NAFLD patients [10,11]
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