Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common chronic liver disease over the past decades. Endoplasmic reticulum stress (ERS) plays a pivotal role during the development of NAFLD. This study aims to analyze the potential role of protein disulfide isomerase A3 precursor (PDIA3), one of the ER chaperones, in free fatty acid-induced cell model of NAFLD. Human liver L02 cell line was treated with sodium palmitate for 24 hours, which developed severe intracellular lipid accumulation. The increased protein level of PDIA3 was detected via immunoblotting analysis in the fat loaded cell models of NAFLD. siRNA-mediated knockdown of PDIA3 in L02 cells not only increased the cellular lipid accumulation, but also exacerbated hepatocytes apoptosis induced by sodium palmitate. Further investigation revealed that knockdown of PDIA3 up-regulated protein expression of fatty acid synthase (FAS), a key enzyme involved in fatty acid synthesis. PDIA3 knockdown also up-regulated key molecules of ERS pathway, including glucose-regulated protein 78 (GRP78), phospho-PKR-like ER kinase (p-PERK), and C/EBP homologous protein (CHOP). Our results suggested that ER chaperone PDIA3 plays a pivotal role in FFA-induced hepatocyte steatosis and apoptosis.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic syndrome characterized by fat accumulation in the liver, with the exception of alcohol and other known causes of liver damage
Oil red O staining demonstrated that lipid droplets were increased when L02 cells were treated with free fatty acids (FFA) for 24 hours (Fig 1A), and the triglyceride assay showed the results (Fig 1B; P
We found that PDIA3, fatty acid synthase (FAS), sterol regulatory element binding protein1 (SREBP1) and ACC1 were all upregulated when L02 cells were treated with FFA for 24 hours. Small interfering RNA (siRNA)-mediated knockdown of PDIA3 resulted in significant increase in FAS protein expression level as compared with negative siRNA after FFA treatment, while SREBP1 and ACC1 showed no statistically difference
Summary
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic syndrome characterized by fat accumulation in the liver, with the exception of alcohol and other known causes of liver damage. The prevalence of NAFLD in Western countries has reached 20–30%, the high prevalence has been observed in Eastern countries [1,2]. NAFLD includes a series of interconnected clinical pathological syndromes, ranging from steatosis to nonalcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and eventually to liver failure or hepatocellular carcinoma [3,4]. The underlying mechanism of NAFLD has not been fully elucidated. PLOS ONE | DOI:10.1371/journal.pone.0133882 July 27, 2015
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