Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease associated with lipotoxicity, lipid peroxidation, oxidative stress, and inflammation. Nuciferine, an active ingredient extracted from the natural lotus leaf, has been reported to be effective for the prevention and treatment of NAFLD. Per-Arnt-Sim kinase (PASK) is a nutrient responsive protein kinase that regulates lipid and glucose metabolism, mitochondrial respiration, and gene expression. The aim of the present study was to investigate the protective effect of nuciferine against NAFLD and its inhibitory effect on PASK, exploring the possible underlying mechanism of nuciferine-mediated inhibition on NAFLD. Relevant biochemical parameters (lipid accumulation, extent of oxidative stress and release of inflammation cytokines) in oleic acid (OA)-induced HepG2 cells that mimicked steatosis in vitro were measured and compared with the control. It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs). The content of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were increased respectively by nuciferine and siRNA PASK without increase in glutathione (GSH). Malondialdehyde (MDA) was decreased respectively by nuciferine and siRNA PASK. In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group. IL-10 was increased by nuciferine and siRNA PASK respectively. Further investigation revealed that nuciferine and siRNA PASK could respectively regulate the expression of target genes involved in lipogenesis and inflammation, suggesting that nuciferine may be a potential therapeutic treatment for NAFLD. Furthermore, the modulated effect of nuciferine on (OA)-induced HepG2 cells lipogenesis and inflammation, which was accompanied with PASK inhibition, was also consistent with siRNA PASK, implying that PASK might play a role in nuciferine-mediated regulation on NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a chronic disorder characterized by hepatic steatosis without significant alcohol consumption
The results showed that the stimulation of hepatic lipogenesis and the release of inflammation cytokines could be effectively reversed by nuciferine in oleic acid (OA)-induced HepG2 cells, which was apparently consistent with the results in siRNA Per-Arnt-Sim kinase (PASK) HepG2 cells
Protein kinase B (Akt) showed significantly decreased in OAinduced HepG2 cells (∗∗P < 0.01 and ∗∗∗P < 0.001), and they both increased when treated with nuciferine and siRNA PASK (∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 vs. OA) (Figures 5A,B). These findings demonstrate that nuciferine could attenuate lipid accumulation by regulating the expression of relevant target genes involved in lipogenesis, which was accompanied with downregulated expression of PASK and was consistent with alterations of relevant genes in siRNA PASK group
Summary
Non-alcoholic fatty liver disease (NAFLD) is a chronic disorder characterized by hepatic steatosis without significant alcohol consumption. NAFLD, which is believed to be associated with central obesity, dyslipidemia, hypertension, hyperglycemia, and other metabolic disorders (Tarantino et al, 2007), is accompanied with a cluster of clinic manifestations ranging from benign hepatocellular steatosis, inflammatory non-alcoholic steatohepatitis (NASH) and fibrosis to cirrhosis. The first “hit” is deposition of free fatty acid and triglyceride in hepatocytes (steatosis), and the second “hit” is the progression of steatosis to NASH. Both progresses are accompanied with the stimulation of hepatic lipogenesis and the release of inflammation cytokines, which are the main causes of NAFLD. Several therapeutic targets have been investigated for the treatment of NAFLD, including the important mediators and nutrient sensors of cellular lipid and glucose homeostasis— AMP-activated protein kinase (AMPK; Dahlhoff et al, 2014) and peroxisome proliferator-activated receptor (PPARα/γ) (Zhao et al, 2014)
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