Nifuroxazide ameliorates lipid and glucose metabolism in palmitate-induced HepG2 cells

Liu, Jingyi; Zhang, Yichen; Song, Li-Ni; Zhang, Lin; Yang, Fengying; Zhu, Xiaozhong; Cheng, Zhiqiang; Cao, Xi; Yang, Jin-Kui

doi:10.1039/c9ra06527j

Cited by 15 publications

(8 citation statements)

References 44 publications

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“…Intracellular lipid accumulation was determined by Oil Red O staining using a previously reported method with slight modifications [ 16 ]. HepG2 cells were plated in a 96-well plate at a density of 1×10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells

et al. 2022

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Background Flavonoids are natural polyphenols found widely in citrus fruit and peel that possess anti-adipogenic effects. On the other hand, the detailed mechanisms for the anti-adipogenic effects of flavonoids are unclear. Objectives The present study observed the anti-adipogenic effects of five major citrus flavonoids, including hesperidin (HES), narirutin (NAR), nobiletin (NOB), sinensetin (SIN), and tangeretin (TAN), on AMP-activated protein kinase (AMPK) activation in palmitate (PA)-treated HepG2 cells. Methods The intracellular lipid accumulation and triglyceride (TG) contents were quantified by Oil-red O staining and TG assay, respectively. The glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) assay. The levels of AMPK, acetyl-CoA carboxylase (ACC), and glycogen synthase kinase 3 beta (GSK3β) phosphorylation, and levels of sterol regulatory element-binding protein 2 (SREBP-2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression were analyzed by Western blot analysis. The potential interaction between the flavonoids and the γ-subunit of AMPK was investigated by molecular docking analysis. Results The flavonoid treatment reduced both intracellular lipid accumulation and TG content in PA-treated HepG2 cells significantly. In addition, the flavonoids showed increased 2-NBDG uptake in an insulin-independent manner in PA-treated HepG2 cells. The flavonoids increased the AMPK, ACC, and GSK3β phosphorylation levels and decreased the SREBP-2 and HMGCR expression levels in PA-treated HepG2 cells. Molecular docking analysis showed that the flavonoids bind to the CBS domains in the regulatory γ-subunit of AMPK with high binding affinities and could serve as potential AMPK activators. Conclusion The overall results suggest that the anti-adipogenic effect of flavonoids on PA-treated HepG2 cells results from the activation of AMPK by flavonoids.

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Section: Methodsmentioning

confidence: 99%

Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells

et al. 2022

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“…It can be seen that insulin-resistant HepG2 cells showed the increased relative mRNA expression level of PCK-1 and G6PC even in the presence of 100 nM insulin (Figure ). These results indicated that the gluconeogenesis rate increased in IR-HepG2 cells due to the blockage of the insulin pathway axis by palmitate, TNF-alpha, and fructose . Treatment of IR-HepG2 cells with GPCK-1 showed nearly 70% downregulation of the PCK-1 gene as compared to the untreated IR cells as shown in Figure A.…”

Section: Resultsmentioning

confidence: 74%

“…These results indicated that the gluconeogenesis rate increased in IR-HepG2 cells due to the blockage of the insulin pathway axis by palmitate, TNF-alpha, and fructose. 38 Treatment of IR-HepG2 cells with GPCK-1 showed nearly 70% downregulation of the PCK-1 gene as compared to the untreated IR cells as shown in Figure 6A. Treatment with EPCK-1 (EscortIV: PCK-1 siRNA(10 nM) conjugate) as a positive control also showed a similar level of downregulation in the PCK-1 gene (0.82 ± 0.20), indicating that the effective delivery and knockdown of the target gene were achieved by our synthesized nanoformulation (0.76 ± 0.28).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Liver Phosphoenolpyruvate Carboxykinase-1 Downregulation via siRNA-Functionalized Graphene Oxide Nanosheets Restores Glucose Homeostasis in a Type 2 Diabetes Mellitus In Vivo Model

et al. 2020

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Metabolic disorders have been increasing at an alarming rate, and one such example of metabolic disorder is type 2 diabetes mellitus (T2DM). Unregulated gluconeogenesis in T2DM results in increased hepatic glucose output that causes fasting and postprandial hyperglycaemia. Extensive proofs have shown that the downregulation of the key rate-limiting enzyme phosphoenolpyruvate carboxykinase-1 (PCK-1) of gluconeogenesis improved glucose homeostasis in vivo. In the present study, we have synthesized and characterized liver-specific stearic acid conjugated octaarginine (StA-R8) functionalized 4arm-2K-PEGamineylated graphene oxide nanosheets (GPR8) for the delivery of siRNA against PCK-1 in T2DM C57BL/6 mice. We found that a single intravenous administration of siRNA (3 mg/kg BW) conjugated to GPR8 (GPR8:PCK-1 siRNA(3 mg/kg BW) conjugate) in an optimized N/P ratio exploited as a therapeutic nanoformulation maintained glucose homeostasis for nearly 4 weeks in the T2DM mice. Efficient silencing of PCK-1 in T2DM liver tissue increased the phosphorylation of serine-256 of FOXO-1, thus showing a marked decrease in hepatic gluconeogenesis. Gluconeogenesis control and consequently glucose output from the liver furthermore partially enhanced liver and muscle insulin sensitivity results in the stimulation of the insulin/AKT-2 signaling pathway which indirectly restored glucose homeostasis in the treated T2DM group. Our therapeutic nanoformulation also improved glycogen storage in the liver and membrane translocation of GLUT4 in the muscle of the treated T2DM group. In conclusion, GPR8:PCK-1 siRNA (3 mg/Kg BW) restored glucose homeostasis by controlling the hepatic glucose production and improved peripheral insulin sensitivity as a consequence of reduced hyperglycemia. Thus, the current approach offered an alternative strategy for the therapeutics for T2DM.

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“…To induce fatty liver conditions, we treated HepG2 and SNU-449 cells with PA, a free fatty acid. PA-treated hepatocytes have been used in previous studies as a fatty liver model to simulate lipid accumulation and IR (Xiao et al 2019;Gao et al 2010;Liu et al 2019;Zhang et al 2019). As shown in Figs.…”

Section: Discussionmentioning

confidence: 99%

Dehydrocostus lactone ameliorates lipid accumulation, insulin resistance, and endoplasmic reticulum stress in palmitate-treated hepatocytes

Hong

Lee²,

Kim³

et al. 2022

J Anal Sci Technol

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Fatty liver disease is caused by lipid accumulation in the liver, insulin resistance (IR), reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress. Dehydrocostus lactone (DHE) has anticancer, anti-inflammatory, and anti-ulcer effects. However, its effects on hepatic steatosis and IR remain unclear. In this study, we investigated whether DHE has antisteatotic effect on fatty liver in vitro. Hepatocytes HepG2 and SNU-449 cells were exposed to 0.25 mM palmitate (PA), and then antisteatotic effect was evaluated by treatment with 10 μM DHE. DHE treatment reduced lipid accumulation and lipogenesis factor protein levels, compared with PA-treated hepatocytes. DHE treatment also decreased gluconeogenesis marker expression and recovered IR in PA-treated hepatocytes, and promoted glucose uptake in PA-treated HepG2 cells. Additionally, the levels of ROS and ER stress factors in PA-treated HepG2 cells were reduced by DHE treatment, compared with PA-treated HepG2 cells. Overall, DHE decreased lipid accumulation and lipogenesis factors as well as recovered IR, gluconeogenesis, and glucose uptake by reducing ER stress and ROS levels in PA-treated hepatocytes. Thus, DHE is a potential antisteatotic agent.

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Nifuroxazide ameliorates lipid and glucose metabolism in palmitate-induced HepG2 cells

Abstract: Inflammation constitutes an important component of non-alcoholic fatty liver disease.

Cited by 15 publications

References 44 publications

Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells

Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells

Liver Phosphoenolpyruvate Carboxykinase-1 Downregulation via siRNA-Functionalized Graphene Oxide Nanosheets Restores Glucose Homeostasis in a Type 2 Diabetes Mellitus In Vivo Model

Dehydrocostus lactone ameliorates lipid accumulation, insulin resistance, and endoplasmic reticulum stress in palmitate-treated hepatocytes

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