Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression
<p>BPA-induced cytotoxicity and ROS production: (<b>a</b>) Cells were incubated at different concentrations of BPA for 24 h. Cell viability was measured using an MTT assay; (<b>b</b>) cells were pretreated with 2′, 7′-dichlorofluorescin diacetate for 45 min and loaded with BPA for 6 h. Intracellular ROS levels were determined according to fluorescence intensity. The boxplots present the median (central horizontal line), 25th and 75th quartiles (upper and lower limits of the box), and the maximum and minimum range values (error bars). The results are expressed as the mean ± SD of six independent experiments. * <span class="html-italic">p</span> < 0.05 vs. control (without BPA) group.</p> "> Figure 2
<p>BPA increases hepatic lipid accumulation and fatty acid uptake: (<b>a</b>) Cells were treated with different doses of BPA plus FFAs (0.5 mM). Lipid droplets were stained using Oil Red O. The quantity of dye extracted from the stained cells was measured using spectrophotometry (below); (<b>b</b>) fatty acid uptake was determined using flow cytometry after exposure to BPA, in the absence or presence of LacCer, for 6 h. The histogram shows the mean of the fluorescence intensity results (below). The results are expressed as the mean ± SD of six independent experiments. * <span class="html-italic">p</span> < 0.05 vs. control (without BPA) group.</p> "> Figure 3
<p>Regulation of ROS levels ameliorated BPA-induced fatty acid uptake and lipid droplet deposition in HUH-7 cells: (<b>a</b>) Cells were pretreated with 2′, 7′-dichlorofluorescin diacetate and NAC (3 mM) for 45 min, before being loaded with the indicated concentrations of BPA for 6 h. Intracellular ROS levels were determined based on fluorescence intensity; (<b>b</b>) cells were treated with BPA after pretreatment with FFAs (0.5 mM) or NAC (3 mM). The accumulation of lipid droplets was assessed using AdipoRed staining; (<b>c</b>) fatty acid uptake was determined using flow cytometry after exposure to BPA (50 μM) for 6 h, in the absence or presence of NAC pretreatment; (<b>d</b>) the mean of the fluorescence intensity results (bottom right). The results are expressed as the mean ± SD of six independent experiments. * <span class="html-italic">p</span> < 0.05 vs. control (without BPA and NAC) group.</p> "> Figure 3 Cont.
<p>Regulation of ROS levels ameliorated BPA-induced fatty acid uptake and lipid droplet deposition in HUH-7 cells: (<b>a</b>) Cells were pretreated with 2′, 7′-dichlorofluorescin diacetate and NAC (3 mM) for 45 min, before being loaded with the indicated concentrations of BPA for 6 h. Intracellular ROS levels were determined based on fluorescence intensity; (<b>b</b>) cells were treated with BPA after pretreatment with FFAs (0.5 mM) or NAC (3 mM). The accumulation of lipid droplets was assessed using AdipoRed staining; (<b>c</b>) fatty acid uptake was determined using flow cytometry after exposure to BPA (50 μM) for 6 h, in the absence or presence of NAC pretreatment; (<b>d</b>) the mean of the fluorescence intensity results (bottom right). The results are expressed as the mean ± SD of six independent experiments. * <span class="html-italic">p</span> < 0.05 vs. control (without BPA and NAC) group.</p> "> Figure 4
<p>NAC inhibited the C/EBPα and CD36 lipid-related endocytosis pathway, which was upregulated by BPA exposure. Cells were treated with the indicated concentrations of BPA for 24 h. The (<b>a</b>) mRNA and (<b>b</b>) protein expression levels of CD36, SR-A1, and SR-B1 were assessed using RT-qPCR and immunoblotting, respectively. (<b>c</b>) To determine whether BPA exposure increases CD36 expression by increasing ROS production, cells were pretreated with or without NAC (3 mM) for 1 h. The protein expression levels of CD36, C/EBPα, and CHOP were determined using immunoblotting. Protein expression levels were normalized to α-tubulin. Data are shown as the mean ± SD of three independent experiments. * <span class="html-italic">p</span> < 0.05 vs. vehicle control group.</p> "> Figure 5
<p>Regulation of ROS levels attenuated BPA-induced hepatic lipid accumulation and liver fibrosis. Eight-week-old C57BL/6 mice were administered an ND, HFCCD, BPA + HFCCD (50 μg/kg/day), or NAC (1 mg/mL, dissolved in drinking water) + BPA (50 μg/kg/day) + HFCCD for 8 weeks: (<b>a</b>) Images of liver tissues isolated from 8-week-old mice fed an ND, HFCCD, BPA + HFCCD, or NAC + BPA + HFCCD for 8 weeks, respectively. Sections of liver tissue were exposed to H&E staining, Masson’s trichrome staining (collagen fibers stained blue), Oil red O staining, and immunohistochemical staining (collagen 1). Scale bar: 200 μm. Protein expression of (<b>b</b>) CHOP, (<b>c</b>) CD36, and (<b>d</b>) α-SMA and cleaved caspase 3 (CL-Caspase3) in liver tissue was measured using western blot. Protein expression levels were normalized to α-tubulin. Data are shown as the mean ± SD of three independent experiments. * <span class="html-italic">p</span> < 0.05 vs. ND group.</p> "> Figure 5 Cont.
<p>Regulation of ROS levels attenuated BPA-induced hepatic lipid accumulation and liver fibrosis. Eight-week-old C57BL/6 mice were administered an ND, HFCCD, BPA + HFCCD (50 μg/kg/day), or NAC (1 mg/mL, dissolved in drinking water) + BPA (50 μg/kg/day) + HFCCD for 8 weeks: (<b>a</b>) Images of liver tissues isolated from 8-week-old mice fed an ND, HFCCD, BPA + HFCCD, or NAC + BPA + HFCCD for 8 weeks, respectively. Sections of liver tissue were exposed to H&E staining, Masson’s trichrome staining (collagen fibers stained blue), Oil red O staining, and immunohistochemical staining (collagen 1). Scale bar: 200 μm. Protein expression of (<b>b</b>) CHOP, (<b>c</b>) CD36, and (<b>d</b>) α-SMA and cleaved caspase 3 (CL-Caspase3) in liver tissue was measured using western blot. Protein expression levels were normalized to α-tubulin. Data are shown as the mean ± SD of three independent experiments. * <span class="html-italic">p</span> < 0.05 vs. ND group.</p> "> Figure 6
<p>The proposed mechanism of BPA coupled with a high-fat diet in enhancing ROS-induced hepatic lipid accumulation and liver fibrosis: BPA + HFCCD increases intracellular ROS production, which induces the expression of CCAAT-enhancer-binding protein α (C/EBPα) and CD36, and promotes free fatty acid uptake. BPA exposure aggravates HFCCD-induced liver damage, leading to cleaved caspase-3 activation for apoptosis, steatohepatitis, and acceleration of the fibrotic process (due to α-SMA overexpression). The figure was created using Biorender.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemical Reagents and Cell Line
2.2. Cell Viability Assay
2.3. Intracellular TG Levels and Lipid Staining
2.4. Determination of Intracellular Fatty Acid Uptake
2.5. Measurement of Intracellular ROS
2.6. Western Blotting and Immunofluorescence
2.7. RNA Extraction and Reverse Transcription–Quantitative Polymerase Chain Reaction (RT-qPCR)
2.8. Animals and Experimental Design
2.9. Staining for Fibrosis in Hepatic Tissue
2.10. Biochemical Assays
2.11. Statistical Analysis
3. Results
3.1. BPA Treatment Induced Cell Death and Increased Intracellular ROS Production
3.2. BPA Treatment Enhanced Accumulation and Uptake of Lipid Droplets
3.3. N-Acetylcysteine (NAC) Suppresses BPA-Induced Fatty Acid Uptake and Lipid Accumulation
3.4. BPA Induced Fatty Acid Uptake by Modulating CD36 Expression
3.5. BPA Enhanced Hepatic Pathological Progression in Mice
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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ND | HFCCD | BPA + HFCCD | NAC + BPA + HFCCD | |
---|---|---|---|---|
Initial body wt (g) | 24.0 ± 1.3 | 23.6 ± 0.6 | 24.0 ± 1.7 | 24.0 ± 0.5 |
Body wt after 4 weeks of the HFCCD diet (g) | 27.2 ± 1.2 b | 27.2 ± 0.9 b | 29.5 ± 1.8 a | 26.2 ± 0.5 b |
Final body wt (g) | 28.7 ± 2 b | 28.8 ± 1.3 b | 25.9 ± 0.4 a | 28.1 ± 1.6 b |
Liver wt (g) | 1.046 ± 0.027 c | 1.301 ± 0.073 b | 1.549 ± 0.135 a | 1.403 ± 0.091 b |
Liver wt/ body wt (%) | 3.665 ± 0.239 c | 4.539 ± 0.416 b | 6.004 ± 0.434 a | 4.997 ± 0.224 b |
Spleen wt (g) | 0.077 ± 0.006 c | 0.099 ± 0.005 b | 0.117 ± 0.002 a | 0.098 ± 0.010 b |
Spleen wt/ body wt (%) | 0.268 ± 0.023 c | 0.346 ± 0.028 b | 0.452 ± 0.016 a | 0.350 ± 0.052 b |
Epididymal fat wt (g) | 0.751 ± 0.089 | 0.795 ± 0.075 | 0.864 ± 0.271 | 0.662 ± 0.091 |
Epididymal fat wt/ body wt (%) | 2.646 ± 0.464 | 2.761 ± 0.178 | 3.353 ± 1.062 | 2.351 ± 0.239 |
Brown fat wt (g) | 0.119 ± 0.019 a | 0.112 ± 0.009 a | 0.078 ± 0.016 b | 0.108 ± 0.009 a |
Brown fat wt/ body wt (%) | 0.415 ± 0.065 a | 0.390 ± 0.028 a | 0.302 ± 0.028 b | 0.381 ± 0.072 a |
ND | HFCCD | BPA + HFCCD | NAC + BPA + HFCCD | |
---|---|---|---|---|
Serum | ||||
ALT (U/L) | 26.20 ± 4.21 b | 63.40 ± 15.82 a | 93.80 ± 34.58 a | 52.60 ± 11.90 a |
Triglycerides (mg/dL) | 69.4 ± 7.83 a | 19.20 ± 4.32 b | 42.00 ± 12.14 a | 73.40 ± 32.21 a |
Total cholesterol (mg/dL) | 134.40 ± 13.83 b | 164.40 ± 27.93 b | 280.20 ± 35.72 a | 131.20 ± 16.96 b |
Blood glucose (mg/dL) | 152.67 ± 33.63 | 148.00 ± 5.93 | 155.00 ± 18.81 | 143.17 ± 7.60 |
Insulin (ng/mL) | 0.177 ± 0.081 c | 0.418 ± 0.13 b | 0.651 ± 0.205 a | 0.374 ± 0.091 b |
HOMA | 1.421 ± 0.453 c | 3.466 ± 1.023 b | 5.717 ± 2.169 a | 3.027 ± 0.774 b |
Liver | ||||
Triglycerides (mg/g of tissue) | 43.17 ± 9.66 | 57.36 ± 12.52 | 55.44 ± 10.40 | 47.01 ± 8.06 |
Total cholesterol (mg/g of tissue) | 6.12 ± 0.74 c | 51.74 ± 10.18 b | 70.50 ± 5.44 a | 50.8 ± 10.81 b |
8-OHdG (ng/g of tissue) | 0.577 ± 0.135 c | 1.158 ± 0.148 b | 2.207±0.219 a | 1.224 ± 0.281 b |
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Lee, J.-L.; Wang, Y.-C.; Hsu, Y.-A.; Chen, C.-S.; Weng, R.-C.; Lu, Y.-P.; Chuang, C.-Y.; Wan, L. Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression. Toxics 2022, 10, 208. https://doi.org/10.3390/toxics10050208
Lee J-L, Wang Y-C, Hsu Y-A, Chen C-S, Weng R-C, Lu Y-P, Chuang C-Y, Wan L. Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression. Toxics. 2022; 10(5):208. https://doi.org/10.3390/toxics10050208
Chicago/Turabian StyleLee, Jyun-Lin, Yao-Chien Wang, Yu-An Hsu, Chih-Sheng Chen, Rui-Cian Weng, Yen-Pei Lu, Chun-Yu Chuang, and Lei Wan. 2022. "Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression" Toxics 10, no. 5: 208. https://doi.org/10.3390/toxics10050208