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. 2018 Dec 19;19(12):4126.
doi: 10.3390/ijms19124126.

Isoquercetin Improves Hepatic Lipid Accumulation by Activating AMPK Pathway and Suppressing TGF-β Signaling on an HFD-Induced Nonalcoholic Fatty Liver Disease Rat Model

Guohong Qin  1   2   3 , Ji Ma  4   5   6 , Qiongshan Huang  7   8   9 , Hongli Yin  10   11   12 , Jichun Han  13   14   15 , Maoru Li  16   17   18 , Yang Deng  19   20   21 , Bing Wang  22   23   24 , Waseem Hassan  25 , Jing Shang  26   27   28
Affiliations

Isoquercetin Improves Hepatic Lipid Accumulation by Activating AMPK Pathway and Suppressing TGF-β Signaling on an HFD-Induced Nonalcoholic Fatty Liver Disease Rat Model

Guohong Qin et al. Int J Mol Sci. .

Abstract

Isoquercetin (IQ), a glucoside derivative of quercetin, has been reported to have beneficial effects in nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the potential improvement of IQ in liver lipid accumulation, inflammation, oxidative condition, and activation in Kupffer cells (KCs) on a high-fat diet (HFD) induced NAFLD models. Male Sprague-Dawley (SD) rats were induced by HFD, lipopolysaccharides/free fatty acids (LPS/FFA) induced co-culture cells model between primary hepatocytes and Kupffer cells was used to test the effects and the underlying mechanism of IQ. Molecular docking was performed to predict the potential _target of IQ. Significant effects of IQ were found on reduced lipid accumulation, inflammation, and oxidative stress. In addition, AMP-activated protein kinase (AMPK) pathway was activated by IQ, and is plays an important role in lipid regulation. Meanwhile, IQ reversed the increase of activated KCs which caused by lipid overload, and also suppression of Transforming growth factor beta (TGF-β) signaling by TGF-β Recptor-1 and SMAD2/3 signaling. Finally, TGF-βR1 and TGF-βR2 were both found may involve in the mechanism of IQ. IQ can improve hepatic lipid accumulation and decrease inflammation and oxidative stress by its activating AMPK pathway and suppressing TGF-β signaling to alleviate NAFLD.

Keywords: AMPK; Kupffer cell; NAFLD; TGF-β; isoquercetin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Isoquercetin (IQ) improves the condition of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rats by decreasing body weight and lipid accumulation. (A) The timelines and intragastrical administration schedule of various compounds used in the study; (B) the body weight curves of different groups used in the study; (C) the body weight gain/day during treatment intervention; (D) the serum triglyceride (TG); (E) demonstrated the haematoxylin and eosin stain (H&E) of the liver; (F) demonstrated the liver weight; (G) demonstrated the oil red stain of the liver; (H) illustrated the liver TG. The data represents ± SD. p < 0.05 was considered as statistically significant. # p < 0.05, ### p < 0.001 represent compared with normal diet (ND) group. * p < 0.05, ** p < 0.01, *** p < 0.001 represent compared with HFD group. The significant statistical difference as calculated by one-way ANOVA with Tukey’s post hoc test. (n = 6 each group).
Figure 2
Figure 2
Effects of IQ on anti-oxidative stress, serum cytokine array, inflammation and regulation of Kupffer cell markers. (A) Illustrated the hepatic reactive oxygen species (ROS); (B) illustrated the hepatic superoxide dismutase (SOD); (C) illustrated the serum malondialdehyde (MDA); (D) the results of cytokine array, illustrated the graphical representation of interleukin (IL) family cytokine, cytokine-induced neutrophil chemoattractant (CINC) family, growth factors, chemokines, and matrix metalloproteinase (MMP) related cytokines; (E) immunohistochemical pictographs CD 68+ stain of liver; (F) western blotting analyses the changes of CD68 in liver; (G) mRNA expression levels of interleukin 1 β(IL1 β), IL-6, tumor necrosis factor-α (TNF-α) in the liver. The data represents ± SD. p < 0.05 was considered as statistically significant. # p < 0.05, ### p < 0.001 represent compared with the ND group. ** p < 0.01, *** p < 0.001 represent compared with HFD group. The significant statistical difference as calculated by one-way ANOVA with Tukey’s post hoc test. (n = 6 each group).
Figure 3
Figure 3
IQ enhances the AMP-activated protein kinase (AMPK) phosphorylation via Liver kinase β1 (LKβ1) upstream. (A) Western blot analysis of AMPK, phospho-AMPK (p-AMPK), Acetyl-CoA carboxylase (ACC), phospho-ACC (p-ACC), Liver kinase β1 (LKβ1), Calcium/calmodulin-dependent protein kinase kinase-1 (CaMKK1), Nuclear factor-κB (NF-κB), and Peroxisome proliferator-activated receptor alpha (PPAR-α); (B) representative blot for AMPK, p-AMPK in lipopolysaccharides/free fatty acids (LPS/FFA) induced in vitro co-culture model. ## p < 0.01, ### p < 0.001 represent compared with control. ** p < 0.01, *** p < 0.001 represent compared with model. The significant statistical difference as calculated by one-way ANOVA with Tukey’s post hoc test.
Figure 4
Figure 4
IQ suppresses TGF-β release, downregulate TGF-βR1 in HFD fed rats and co-culture model. (A) Representative blots of TGF-βR1 and SMAD2/3 in HFD group; (B) shows the TGF-β level in LPS/FFA induced co-culture cell by ELISA test and the mRNA expression of TGF-βR1 of LPS/FFA induced co-culture cell; (C) shows the representative blots of TGF-βR1 and SMAD2/3 in LPS/FFA induced co-culture model; (D) in vitro effects of IQ in TGF-β induced cultured cells (L02) on TGF-βR1 and SMAD2/3. # p < 0.05, ## p < 0.01, ### p < 0.001 represent compared with control. *** p < 0.001 represent compared with model. The significant statistical difference as calculated by one-way ANOVA with Tukey’s post hoc test.
Figure 5
Figure 5
Predict the potential mechanism of IQ. (A) Docking results of IQ with AMPK. Amino acid residues which are thought to interact with IQ are shown in 2D representation using LigX in MOE (PDB number: 2YA3); (B) docking results of IQ with the TGF-β receptor, TGF-βR1 (access code: 1VJY.pdb), and TGF-βR2 (access code: 1KTZ.pdb) Amino acid residues, which are thought to interact with IQ are shown in two-dimensional (2D) representation using LigX in MOE. Hydrogen bonding is shown in dotted lines along with percentages.
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