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Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells.

Zhang DD, Zhang JG, Wu X, Liu Y, Gu SY, Zhu GH, Wang YZ, Liu GL, Li XY - Front Pharmacol (2015)

Bottom Line: It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs).In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China.

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.

No MeSH data available.


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(A) The effect of nuciferine or siRNA PASK on the mRNA level related to inflammation in HepG2 cells. (B,C) The effect of nuciferine and siRNA PASK on the expression of proteins related to inflammation in HepG2 cells. SiRNA PASK HepG2 cells and HepG2 cells incubated with increased concentrations of nuciferine (NF: 10, 25, and 50 μM) both treated with OA (40 μM). The measurement was described in the Section “Materials and Methods”. Values are Mean ± SEM of three independent experiments performed in triplicates. Significant differences with OA group were designated as those ∗P < 0.05 and ∗∗∗P < 0.001. (Control, siRNA scrambled; NF, Nuciferine.)
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Figure 9: (A) The effect of nuciferine or siRNA PASK on the mRNA level related to inflammation in HepG2 cells. (B,C) The effect of nuciferine and siRNA PASK on the expression of proteins related to inflammation in HepG2 cells. SiRNA PASK HepG2 cells and HepG2 cells incubated with increased concentrations of nuciferine (NF: 10, 25, and 50 μM) both treated with OA (40 μM). The measurement was described in the Section “Materials and Methods”. Values are Mean ± SEM of three independent experiments performed in triplicates. Significant differences with OA group were designated as those ∗P < 0.05 and ∗∗∗P < 0.001. (Control, siRNA scrambled; NF, Nuciferine.)

Mentions: To further deliberate the possible mechanism underlying the nuciferine-mediated effect on inflammation, the alteration of genes involved in release of inflammatory cytokines was measured. The expression of TNF-α (∗P < 0.05) and NF-κB (∗∗∗P < 0.001) mRNA in HepG2 cells treated with OA was increased significantly as compared with that in the control. Meanwhile, siRNA PASK could significantly inhibited the level of TNF-α (∗P < 0.05 vs. OA) and NF-κB (∗∗∗P < 0.001 vs. OA) mRNA compared with the OA-treated cells. However, addition of nuciferine (10, 25, and 50 μM) showed no statistically significant decrease in expression of TNF-α mRNA though it could significantly downregulate the NF-κB mRNA expression (∗∗∗P < 0.001 vs. OA) (Figure 9A). In addition, the expression of NF-κB (∗∗∗P < 0.001 vs. control) in HepG2 cells treated with OA was upregulated significantly as compared with the control, and this upregulation could be successfully reverted by nuciferine (10, 25, and 50 μM; ∗∗∗P < 0.001 vs. OA) and siRNA PASK (∗∗∗P < 0.001 vs. OA) (Figures 9B,C). These data suggest that inhibition of TNF-α and NF-κB might be the potential mechanism underlying the regulatory effect of nuciferine on inflammation, which was accompanied with downregulated expression of PASK.


Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells.

Zhang DD, Zhang JG, Wu X, Liu Y, Gu SY, Zhu GH, Wang YZ, Liu GL, Li XY - Front Pharmacol (2015)

(A) The effect of nuciferine or siRNA PASK on the mRNA level related to inflammation in HepG2 cells. (B,C) The effect of nuciferine and siRNA PASK on the expression of proteins related to inflammation in HepG2 cells. SiRNA PASK HepG2 cells and HepG2 cells incubated with increased concentrations of nuciferine (NF: 10, 25, and 50 μM) both treated with OA (40 μM). The measurement was described in the Section “Materials and Methods”. Values are Mean ± SEM of three independent experiments performed in triplicates. Significant differences with OA group were designated as those ∗P < 0.05 and ∗∗∗P < 0.001. (Control, siRNA scrambled; NF, Nuciferine.)
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getmorefigures.php?uid=PMC4612658&req=5

Figure 9: (A) The effect of nuciferine or siRNA PASK on the mRNA level related to inflammation in HepG2 cells. (B,C) The effect of nuciferine and siRNA PASK on the expression of proteins related to inflammation in HepG2 cells. SiRNA PASK HepG2 cells and HepG2 cells incubated with increased concentrations of nuciferine (NF: 10, 25, and 50 μM) both treated with OA (40 μM). The measurement was described in the Section “Materials and Methods”. Values are Mean ± SEM of three independent experiments performed in triplicates. Significant differences with OA group were designated as those ∗P < 0.05 and ∗∗∗P < 0.001. (Control, siRNA scrambled; NF, Nuciferine.)
Mentions: To further deliberate the possible mechanism underlying the nuciferine-mediated effect on inflammation, the alteration of genes involved in release of inflammatory cytokines was measured. The expression of TNF-α (∗P < 0.05) and NF-κB (∗∗∗P < 0.001) mRNA in HepG2 cells treated with OA was increased significantly as compared with that in the control. Meanwhile, siRNA PASK could significantly inhibited the level of TNF-α (∗P < 0.05 vs. OA) and NF-κB (∗∗∗P < 0.001 vs. OA) mRNA compared with the OA-treated cells. However, addition of nuciferine (10, 25, and 50 μM) showed no statistically significant decrease in expression of TNF-α mRNA though it could significantly downregulate the NF-κB mRNA expression (∗∗∗P < 0.001 vs. OA) (Figure 9A). In addition, the expression of NF-κB (∗∗∗P < 0.001 vs. control) in HepG2 cells treated with OA was upregulated significantly as compared with the control, and this upregulation could be successfully reverted by nuciferine (10, 25, and 50 μM; ∗∗∗P < 0.001 vs. OA) and siRNA PASK (∗∗∗P < 0.001 vs. OA) (Figures 9B,C). These data suggest that inhibition of TNF-α and NF-κB might be the potential mechanism underlying the regulatory effect of nuciferine on inflammation, which was accompanied with downregulated expression of PASK.

Bottom Line: It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs).In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus