Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Article Screening and Selection
2.3. Data Extraction
3. Results
3.1. Search Results
3.2. Results Organization
3.3. Studies Evaluating GSH Levels in Animal Models of MASLD
3.3.1. Studies on Rat Models
3.3.2. Studies on Mice Models
3.4. Studies Evaluating GSH Levels in Cell Models of MASLD
3.5. Studies Evaluating Cys, CysGly, Hcy, and Total Thiols in In Vivo and In Vitro Models of MASLD
3.6. Studies Evaluating LMW Thiols in Humans
3.6.1. Observational Studies
3.6.2. Clinical Trials
4. Discussion
4.1. Qualitative Analysis
4.2. Limitations of the Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Strain | Diet and/or Supplements | Study Length (Weeks) | GSH and GSSG Levels in Model(s) (Mean ± Standard Deviation) | GSH in Normal Diet (ND) (Mean ± Standard Deviation) | Method | p-Values | Ref. |
---|---|---|---|---|---|---|---|
Not reported (nr) | ND, high-fructose diet (HFruD), HFruD + allopurinol (A), HFruD + metformin (MET), HFruD + vitamin E (VitE), HFruD + MET + VitE, HFruD + A + MET + VitE | 4 | Hepatic GSH (mg/g tissue): HFruD: 107 ± 1.70 HFruD + A: 119.3 ± 2.77 HFruD + MET: 128.9 ±1.44 HFruD + VitE: 122.9 ± 1.76 HFruD + MET + VitE: 122.5 ± 1.67 HFruD + A + MET + VitE: 129.8 ± 1.30 | Hepatic GSH (mg/g tissue): 129.7 ± 1.14 mg/g tissue | Ellman | Lower in HFruD vs ND and vs. all groups of treatments (p < 0.05) | [28] |
Wistar and Zucker | ND, methionine and choline-deficient (MCD) diet on Wistar | 3 | Hepatic tGSH (nmol/mg protein): MCD: 16.1 ± 0.9 Lean Zucker: 35.7 ± 2.0 Obese Zucker: 31.2 ± 2.7 | Hepatic tGSH (nmol/mg protein): 37.5 ± 1.6 | Enzymatic recycling | Lower in MCD vs. ND (p < 0.05) | [29] |
Sprague–Dawley | ND, cholesterol and fat-enriched (HCHF) diet, HCHF + carvedilol (CARV), HCHF + nicorandil (NICO) | 4 (HCHF) + 4 (ND + No drug/HCHF + CARV/NICO) | Hepatic GSH (mmol/mg protein): HCHF: 28.38 + 2.120 HCHF + CARV: 43.08 + 5.301 HCHF + NICO: 33.13 + 2.446 | Hepatic GSH (mmol/mg protein): 52.67 + 0.835 | Ellman | Lower in HCHF vs. ND and vs. HCHF + CARV and HCHF + NICO (p < 0.05) | [30] |
Sprague–Dawley | ND, high-fat diet (HFD), HFD + mulberry extract (MB), and silk amino acids (SA) mixtures | 12 | Hepatic GSH (μmol/g protein): HFD: 22.8 ± 2.1 HFD + MB/SA 1:3 low dosage: 25.1 ± 2.2 HFD + MB/SA 1:3 high dosage: 27.7 ± 2.1 HFD + MB/SA 1:5 low dosage: 23.5 ± 2.5 HFD + MB/SA 1:5 high dosage: 24.8 ± 2.2 | Hepatic GSH (μmol/g protein): 24.9 ± 2.3 | Ellman | - Lower in HFD vs. ND (p < 0.05) - Recovery with all treatments (mainly with SA 1:3) (p < 0.05) | [31] |
Wistar | ND, HFruD, HFruD + chrysin (chry) | 16 | Hepatic GSH (μg/mg tissue protein): HFruD: 363.7 ± 71.67 HFruD + chry (25 mg/kg; 50 mg/kg; 100 mg/kg): 553.9 ± 32.35; 714.2 ± 39.75; 844.2 ± 89.6 | Hepatic GSH (μg/mg tissue protein): 901 ± 97.45 | Ellman | - Lower in HFD vs. ND (p < 0.001) - Recovery with treatments at higher doses (p < 0.05, p < 0.001) | [32] |
Wistar | ND, HFD, HFD + MET, HFD + Cassia semens (Cs) | 12 | Hepatic GSH (mg/g protein): HFD: 4.55 ± 0.91 HFD + MET: 6.68 ± 1.26 Cs (0.5 g/kg; 1 g/kg; 2 g/kg): 5.88 ± 1.06; 6.79 ± 0.93; 7.79 ± 1.48 | Hepatic GSH (mg/g protein): 9.76 ± 1.32 | Ellman | - Lower in HFD vs. ND - Dose-dependent recovery with all treatments (p < 0.05, p < 0.01) | [33] |
Wistar | ND, sucrose (S) | approximately 26 | Hepatic GSH (nmol/mg tissue): S: 7.05 ± 0.76 Hepatic GSSG (nmol/mg tissue): S: 1.28 ± 0.06 Hepatic GSH + 2× GSSG (nmol GSH units/mg tissue): S: 8.33 ± 0.75 Hepatic GSH/GSSG: S: 5.57 ± 0.67 | Hepatic GS (nmol/mg tissue): 18.54 ± 0.41 Hepatic GSSG (nmol/mg tissue): 2.38 ± 0.12 Hepatic GSH + 2× GSSG (nmol GSH units/mg tissue): 20.92 ± 0.50 Hepatic GSH/GSSG: 7.83 ± 0.28 | Fluorimetric | Lower GSH, GSSG and GSH + 2× GSSG in sucrose vs. ND (p < 0.05) | [34] |
Wistar | ND, high-fat cholesterol diet (HFCD), ND + cranberry (cra), HFCD + cra | 8 | Hepatic GSH (pg/mg protein): HFCD: 9.66 ± 0.60 ND + cra (100 mg/kg): 69.8 ± 3.34 protein HFCD + cra (50 mg/kg; 100 mg/kg): 19.01 ± 1.33; 34.47 ± 0.74 | Hepatic GSH (pg/mg protein): 43.22 ± 1.42 | Ellman | - Lower in HFD vs. ND - Dose-dependent recovery with all treatments (p < 0.05) | [35] |
Sprague-Dawley | ND, ovariectomized (OVX) + ND, OVX + high-fat and high-fructose diet (OVX + HFHF) | 4 | Hepatic GSH (nmol/mg protein): OVX + ND: 55.21 ± 1.40 OVX + HFHF: 46.01 ± 0.91 | Hepatic GSH (nmol/mg protein): 57.94 ± 0.32 | Ellman | - Lower in OVX + ND vs. ND (p < 0.01) - Lower in OVX + HFHF vs. OVX + ND (p < 0.01) | [36] |
nr | ND, HFD, ND + ethanolic extract of garden cress seeds, HFD + Garden Cress (GC) | 12 | Hepatic GSH (pg/g tissue) HFD: 29.64 ± 0.91 GC: 42.59 ± 1.64 HFD + GC: 38.18 ± 1.77 | Hepatic GSH (pg/g tissue) 41.58 ± 2.48 | Immunosorbent | Hepatic GSH: Lower in HFD vs. ND and vs. treatment group (p < 0.05) | [37] |
Wistar | ND, HFD, HFD + pioglitazone (PIO), HFD + Ruzu herbal bitters (RUZU), HFD + fenofibrate (FENO) | 12 | Hepatic GSH (nmol/mg protein): HFD: 72.24 ± 5.15 HFD + PIO: 112.10 ± 3.79 HFD + RUZU: 119.19 ± 9.21 HFD + FENO: 151.53 ± 19.69 | Hepatic GSH (nmol/mg protein): 112.18 ± 6.18 | Enzymatic recycling | - Lower in HFD vs. ND (p < 0.05) - Recovery with all treatments (p < 0.05) | [38] |
Wistar | HFD, HFD + MET, HFD + pentoxifylline (PTX) + MET, HFD + cilostazol (CLS) + MET, HFD + sildenafil (SLD) + MET | 16 | Hepatic GSH (mmol/g tissue): HFD + MET: 45.9 ± 2.0 HFD + PTX + MET: 69.9 ± 2.8 HFD + CLS + MET: 42.3 ± 5.0 HFD + SLD + MET: 50.5 ± 3.18 | Hepatic GSH (mmol/g tissue): 74.4 ± 3.8 | Ellman | - Lower in HFD vs. ND (p < 0.05) - Recovery with all treatments (p < 0.05) | [39] |
Sprague-Dawley | ND, HFD, ND + lycopene (lyc), HFD + lyc | 8 | Hepatic GSH (pg/mg protein): HFD: 2.5 ± 0.35 ND + lyc: 13.0 ± 1.7 HFD + lyc: 8.3 ± 0.7 | Hepatic GSH (pg/mg protein): 12.4 ± 1.2 | Ellman | - Lower in HFD vs. ND (p < 0.05) - Recovery with treatment (p < 0.05) | [40] |
Wistar | ND, HFD, ND + pectinase treated probiotic banana juice (PPBJ), HFD + PPBJ | 20 | Hepatic GSH (µmol/µg protein): HFD: 0.4 ± 0.21 ND + PPBJ: nr HFD + PPBJ: 1.04 ± 0.04 | nr | Ellman | Lower in HFD vs. treatment control (p < 0.001) | [41] |
Wistar | ND, HFHF, HFHF + MET, HFHF + melatonin (MEL) | 8 | Hepatic GSH (μmol/g tissue): HFHF: 78.32 ± 2.28 HFHF + MET: 99.31 ± 4.68 HFHF + MEL: 104.9 ± 4.24 | Hepatic GSH (μmol/g tissue): 122.2 ± 6.58 | High-performance liquid chromatography (HPLC)-UV | - Lower in HFHF vs. ND (p < 0.05) - Recovery with treatment groups (p < 0.05) | [42] |
Wistar | ND, HFruD, ethanol, HFruD + 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), ethanol + 1,25(OH)2D3 | 8 | Hepatic GSH (nmol/mg protein): HFruD: 19.4 ± 4.03 ethanol: 21.5 ± 5.17 HFruD + 1,25(OH)2D3: 19.5 ± 4.99 ethanol + 1,25(OH)2D3: 26.9 ± 5.70 | Hepatic GSH (nmol/mg protein): 23.9 ± 3.02 | Ellman | Not significant | [43] |
Wistar | ND, HFD, ND + eugenol (EUG), HFD + EUG | 8 | Hepatic GSH (pg/mg protein): HFD: 11.1 ± 1.33 ND + EUG: 48.5 ± 3.24 HFD + EUG: 27.0 ± 2.03 | Hepatic GSH (pg/mg protein): 40.0 ± 5.69 pg/mg protein | Immunosorbent | - Lower in HFD vs. ND (p < 0.05) - Recovery with treatment (p < 0.05) | [44] |
Wistar | ND, HFruD, ND + silymarin (sily), HFruD + sily | 8 | Hepatic GSH (μmol/g tissue): HFruD: 33.93 ± 0.91 ND + Sily (400 mg/kg): 36.53 ± 0.89 HFruD + sily (200 mg/kg; 400 mg/kg): 35.49 ± 0.98; 36.35 ± 0.93 | Hepatic GSH (μmol/g tissue): 37.98 ± 1.07 | Ellman | - Lower in HFruD vs. ND (p < 0.001) - Recovery with treatment groups (p < 0.05, p < 0.01) | [45] |
Wistar | ND, HFD/coconut oil (CO) + streptozotocin (STZ), HFD/thermally oxidized CO (TCO) + STZ | 4 (ND/HFD) + 4 (ND + No drug/HFD + STZ) | Hepatic GSH in 2 different areas (µmol/mg protein): HFD/CO + STZ: 10.85 ± 1.88; 7.15 ± 1.04 HFD/TCO + STZ: 9.53 ± 0.67; 5.52 ± 1.86 | Hepatic GSH (µmol/mg protein): 4.73 ± 0.66 µmol/mg protein | Ellman | Higher in all groups vs. ND (p < 0.01) | [46] |
Wistar | ND, HFruD | 8 12 | Hepatic GSH—8 weeks (µM/100 mg tissue): HFruD (10%; 30%; 60%): 51.58 ± 13.90; 56.61 ± 24.79; 83.95 ± 17.95 Hepatic GSH—12 weeks (µM/100 mg tissue): HFruD (10%; 30%; 60%): 98.33 ± 19.80; 86.11 ± 42.20; 177.67 ± 60.30 | Hepatic GSH (µM/100 mg tissue): 66.95 ± 4.83 (8 weeks) 126.58 ± 18.13 (12 weeks) | Enzymatic recycling | Decreased GSH with concentration and time (p < 0.0001) | [47] |
Sprague-Dawley | ND, HFHF, HFHF + sily, HFHF + celery, HFHF + curcumin (cur) | 16 (ND/HFHF) + 4 (ND/HFHF + No drug/HFHF + sily/HFHF/HFHF + cur) | Hepatic GSH (μmol/g tissue): HFHF: 14.47 ± 0.1 HFHF + sily: 18.44 ± 0.09 HFHF + celery: 21.22 ± 0.12 HFHF + cur: 19.71 ± 0.08 | Hepatic GSH (μmol/g tissue): ND: 25.7 ± 0.24 | HPLC-UV | - Lower in HFHF vs. ND (p < 0.05) - Recovery in treatment groups (p < 0.05) | [48] |
Sprague-Dawley | ND, HFD, HFD + orlistat (O), obese (ob)/HFD + O | 6 (ob/HFD + O), 12 (HFD + O) | Hepatic GSH (nmol/mg protein): HFD: 2.37 ± 0.10 HFD + O: 3.06 ± 0.06 ob/HFD + O: 2.91 ± 0.19 | Hepatic GSH (nmol/mg protein): 3.29 ± 0.08 | Ellman | - Lower in HFD vs. ND (p < 0.05) - Recovery in protective and therapeutic treatment groups (p < 0.05) | [49] |
Wistar | ND, MCD | 2, 4, 8 | Hepatic GSH (nmol/mg protein): MCD 2 wk: 19.33 ± 1.34 MCD 4 wk: 16.18 ± 1.15 MCD 8 wk: 17.99 ± 1.74 | Hepatic GSH (nmol/mg protein): 2 wk: 37.31 ± 1.49 4 wk: 37.66 ± 2.53 8 wk: 36.92 ± 2.51 | Enzymatic recycling | Lower in MCD vs. ND (p < 0.05) | [50] |
Wistar | ND, HFruD, HFruD + chry | 8 | Hepatic GSH (mg/g tissue): HFruD: 9.6 ± 0.64 HFruD + chry (25 mg/kg; 50 mg/kg): 12.18 ± 0.35; 13.06 ± 0.24 | Hepatic GSH (mg/g tissue): 13.9 ± 0.34 | Ellman | - Lower in HFruD vs. ND (p < 0.001) - Recovery in protective and therapeutic treatment groups (p < 0.001) | [51] |
Wistar | ND, obesogenic diet (ObD), ObD + chry | 12 (ND/ObD) + 4 (ND + No drug/ObD/ObD + chry) | Hepatic tGSH (nmol/mg protein): ObD: 21.4 ± 1.8 ObD + chry (25 mg/kg; 50 mg/kg; 75 mg/kg): 23.7 ± 1.9; 24.7 ± 1.9; 25.0 ± 1.7 Hepatic GSH (nmol/mg protein): ObD: 17.5 ± 1.5 Ob/D + chry (25 mg/kg; 50 mg/kg; 75 mg/kg): 20.8 ± 1.7; 22.3 ± 1.8; 22.7 ± 1.6 Hepatic GSSG: ObD: 2.0 ± 0.2 nmol/mg protein; ObD + chry (25 mg/kg; 50 mg/kg; 75 mg/kg): 1.5 ± 0.2; 1.2 ± 0.2; 1.2 ± 0.1 Hepatic GSH/GSSG: ObD: 8.9 ± 0.6 ObD + chry (25 mg/kg; 50 mg/kg; 75 mg/kg): 14.1 ± 1.2; 19.0 ± 2.5; 19.7 ± 1.6 | Hepatic tGSH (nmol/mg protein): 27.7 ± 1.7 Hepatic GSH: 25.6 ± 1.6 Hepatic GSSG: 1.1 ± 0.1 Hepatic GSH/GSSG: 23.6 ± 2.0 | Enzymatic recycling | tGSH and GSH/GSSG: - Lower in ObD vs. ND (p < 0.05) - Recovery in all treatments (p < 0.05) GSH: - Higher in ObD vs. ND (p < 0.05) - Recovery in all treatments (p < 0.05) | [52] |
nr | ND, HFHF, vitamin D (VitD), HFHF + VitD | 10 | Hepatic GSH (mg/g.tissue): HFHF: 3.30 ± 0.20 VitD: 5.57 ± 0.15 HFHF + VitD: 4.61 ± 0.16 | Hepatic GSH (mg/g tissue): 5.56 ± 0.29 mg/g tissue | Ellman | Lower in HFD vs. ND and treatment control (p < 0.05) | [53] |
Wistar | ND, HFD, ND + M. pubescens powder (MP), HFD + MP | 16 | Hepatic GSH (nmol/mg protein): HFD: 48.95 ± 3.64 ND + MP: 78.68 ± 2.31 HFD + MP: 76.19 ± 4.44 | Hepatic GSH (nmol/mg protein): 82.07 ± 4.09 | Ellman | - Lower in HFD vs. ND (p < 0.001) - Recovery in the treatment group (p < 0.01) | [54] |
Strain | Diet and/or Supplements | Study Length (Weeks) | GSH and GSSG Levels in Model(s) (Mean ± Standard Deviation) | GSH in Normal Diet (ND) (Mean ± Standard Deviation) | Method | p-Values | Ref. |
---|---|---|---|---|---|---|---|
C57BL/6J | ND, high-fat and high-fructose diet (HFHF), HFHF + 14-deoxy-11,12-didehydroandrographolide (deAND) | 7 | Hepatic GSH (nmol/mg protein): HFHC: 0.26 ± 0.03 HFHC + 0.05% deAND: 0.24 ± 0.05 HFHC + 0.1% deAND: 0.32 ± 0.04 | Hepatic GSH (nmol/mg protein): 2.81 ± 0.99 | High-performance liquid chromatography-mass spectrometry (HPLC-MS) | Lower in HFHF vs. ND, and vs. HFHF + deAnd at the higher dose (p < 0.05) | [103] |
C57BL/6J | High-fat diet (HFD) + Gongmei White Tea (T1), White Peony Tea (T2), Enshi Yulu Tea (T3), Fried Green Tea (T4), Yihong Tea (T5), Lapsang Souchong Tea (T6), Wuyi Narcissus Tea (T7), Fenghuang Narcissus Tea (T8), Qing Brick Tea (T9), Pu-erh Tea (T10), Yuan’an Luyuan Tea (T11), Mengding Huangya Tea (T12) | 15 | Hepatic GSH (μmol/g protein): HFD: 3.94 ± 1.14 HFD + T1: 3.46 ± 0.79 HFD + T2: 3.76 ± 0.92 HFD + T3: 3.82 ± 0.40 HFD + T4: 2.58 ± 0.65 HFD + T5: 2.16 ± 0.37 HFD + T6: 4.63 ± 1.90 HFD + T7: 4.91 ± 1.62 HFD + T8 5.30 ± 0.98 HFD + T9: 3.80 ± 1.07 HFD + T10: 4.23 ± 0.76 HFD + T11: 4.53 ± 1.36 HFD + T12: 4.37 ± 1.38 | Hepatic GSH (μmol/g protein): 5.26 ± 2.10 | Ellman | Lower in the HFD group vs. ND and ND, and vs. T4, T5, and T8 (p < 0.05) | [104] |
ICR | ND, HFD/ethanol, HFD/ethanol + fenofibrate (F), HFD/ethanol + hesperidin (H), HFD/ethanol + myricetin (M) | Approximately 8 | Hepatic tGSH (nmol/mg protein): HFD/ethanol: 133.91 ± 23.82 HFD/ethanol + F: 92.69 ± 11.56 HFD/ethanol + H (50 mg/kg; 200 mg/kg): 98.83 ± 24.95; 73.71 ± 16.56 HFD/ethanol + M (50 mg/kg; 200 mg/kg): 83.52 ± 11.58; 82.43 ± 17.53 Hepatic GSH (nmol/mg protein): HFD/ethanol: 41.42 ± 9.20 HFD/ethanol + F: 63.58 ± 3.87 HFD/ethanol + H (50 mg/kg; 200 mg/kg): 69.03 ± 9.10; 35.63 ± 4.51 HFD/ethanol + M (50 mg/kg; 200 mg/kg): 48.07 ± 9.19; 48.87 ± 7.35 Hepatic GSSG (nmol/mg protein): HFD/ethanol: 42.11 ± 11.22 HFD/ethanol: + F: 29.11 ± 8.67 HFD/ethanol + H (50 mg/kg; 200 mg/kg): 29.80 ± 8.67; 38.08 ± 6.82 HFD/ethanol + M (50 mg/kg; 200 mg/kg): 35.45 ± 5.76; 33.56 ± 6.18 Hepatic GSH/GSSG: HFD/ethanol: 0.98 ± 0.11 HFD/ethanol: + F: 2.18 ± 0.57 HFD/ethanol + H (50 mg/kg; 200 mg/kg): 2.32 ± 0.31; 0.94 ± 0.48 HFD/ethanol + M (50 mg/kg; 200 mg/kg): 1.35 ± 0.44; 1.45 ± 0.53 | Hepatic tGSH (nmol/mg protein) 133.91 ± 13.74 Hepatic GSH (nmol/mg protein) 104.86 ± 13.01 Hepatic GSSG (nmol/mg protein) 29.05 ± 5.00 Hepatic GSH/GSSG 3.61 ± 1.16 | Enzymatic recycling | GSH, GSH/GSSG: Lower in HFD/ethanol vs. ND and vs. low dose H and vs. F (p < 0.05) | [105] |
CD1 (ICR) | ND, HFD, HFD + metformin (MET), HFD + water chestnut (WC) | 13 | Hepatic GSH (µM/mg tissue): HFD: 10.45 ± 1.80 HFD + MET: 32.31 ± 10.11 HFD + WC (50 mg/kg, 100 mg/kg, 200 mg/kg): 10.74 ± 3.21; 32.31 ± 13.52; 45.49 ± 13.68 | Hepatic GSH (µM/mg tissue): 69.63 ± 10.20 | Ellman | Lowers in HFD vs. ND and vs. treatments at higher doses | [106] |
C57BL/6J | ND, HFD/streptozotocin (STZ), HFD/STZ + swietenine (SW) | 3 (HFD/STZ) + 8 (HFD + STZ/HFD + STZ + SW) | Serum GSH (nmol/µL): HFD/STZ: 0.71 ± 0.18 HFD/STZ + SW: 2.02 ± 0.08 | Serum GSH (nmol/µL): 2.41 ± 0.21 | Ellman | Lower in HFD/STZ vs. ND and vs. treatment (p < 0.0001) | [107] |
C57BL/6 | ND, ND + 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) HFHF, HFHF + AICAR | 10 | Plasma GSH (μg/mg protein): AICAR: 9.80 ± 0.22 HFHF: 5.72 ± 0.17 HFHF + AICAR: 7.63 ± 0.19 | Plasma GSH (μg/mg protein): 9.78 ± 0.20 | Ellman | Lower in HFHF vs. ND and vs. treatment (p < 0.05) | [108] |
Model | Supplements | Study Length (Hours) | GSH and GSSG Levels in Model(s) | GSH in Control Group (Ctrl) | Method | p-Values | Ref. |
---|---|---|---|---|---|---|---|
BRL-3A cells | Ctrl, nonesterified fatty acids (NEFAs) | 12 | Not reported (nr) | nr | Ellman | GSH: Lower in NEFAs vs. Ctrl (p < 0.05) | [58] |
HepG2 cells | Oleic acid (OA), OA + berbamine, OA + fenofibrate (FENO) | 48 | nr | nr | Fluorimetric | GSH: - Lower in OA vs. Ctrl (p < 0.05) - Recovery with treatments at higher dose (p < 0.05) | [162] |
HepG2 cells | OA/tert-butylhydroperoxide (t-BHP), t-BHP + water extract of A. annua | 6 | nr | nr | Ellman | GSH: Lower in t-BHP vs. treatment groups (p < 0.001) | [163] |
HepG2 cells | Ctrl, palmitic acid (PA), phloroglucinol (PHG), PA + PHG, PA + α-lipoic acid (ALA), PA + N-acetylcysteine (NAC) + H2O2 | 16 | nr | nr | Enzymatic recycling | tGSH: Lower in PHG vs. Ctrl (p < 0.05) GSH: - Lower in PA (p < 0.0001) and PHG (p < 0.01) - Recovery dose-dependently with treatments (p < 0.01) GSSG: - Higher in PA vs. Ctrl - Recovery dose-dependently with treatments (p < 0.01) GSH/GSSG: - Lower in PA and PHG vs. Ctrl - Recovery dose-dependently with treatments (p < 0.05) | [164] |
L02 cells | Ctrl, H2O2, H2O2 + Lycii fructus polysaccharide (LFP) | 48 | nr | nr | Ellman | GSH: - Lower in H2O2 vs. Ctrl (p < 0.0001) - Recovery with all treatments (p < 0.01, p < 0.001) | [165] |
L02 cells | Free fatty acids (FFAs), FFAs + malvidin-3-O-glucoside (M3G), FFAs + malvidin-3-O-galactoside (M3Ga), FFAs + buthionine sulfoximine (BSO), FFAs + NAC | 48 | nr | nr | Fluorimetric | GSH: - Lower in FFAs and FFAs + BSO vs. Ctrl (p < 0.05) - Recovery with M3G, M3Ga and NAC (p < 0.05) | [166] |
HepG2 cells | Ctrl, OA, OA + hesperetin (H) | 24 | nr | nr | Ellman | GSH: Lower in OA vs. Ctrl and vs. OA + H (p < 0.05) | [66] |
HepG2 cells | FFAs, FFAs + picroside II (PIC), FFAs + silibinin | 22 | nr | nr | Enzymatic recycling | tGSH: - Lower in FFAs vs. Ctrl (p < 0.01) - Recovery with treatments (p < 0.05) GSH/GSSG: - Lower in FFAs vs. Ctrl (ns) and vs. FFAs + PIC (p < 0.01) | [167] |
L02 cells | Ctrl, 5% fat emulsion (FE), FE + Jiuzhuan Huangjing pills | 24 | nr | nr | Ellman | GSH: - Lower in FE vs. Ctrl (p < 0.05) - Recovery with treatment at higher doses (p < 0.01) | [68] |
Primary mouse hepatocytes | Ctrl, fructose (Fru), Fru + carminic acid (CA) | nr | nr | nr | Ellman | GSH: Lower in Fru vs. Ctrl and Fru + CA groups (p < 0.05) | [168] |
HepG2 cells | Ctrl, FFAs, FFAs + xiaoheiyao (XHY-1) | 24 | nr | nr | Enzymatic recycling | GSH/GSSG: - Lower in FFAs vs. Ctrl - Recovery with treatment at higher doses (0.05) | [169] |
HepG2 cells subcultured on rat liver biological matrix scaffolds | Ctrl, FFAs, FFAs + baicalin | 192 | nr | nr | Ellman | GSH: - Lower in FFAs vs. Ctrl (p < 0.05) - Recovery with treatment (p < 0.01) | [170] |
L02 cells | Ctrl, PA | nr | nr | nr | Enzymatic recycling | GSH/GSSG: Lower in PA vs. Ctrl (significance nr) | [171] |
HepG2 spheroids | Ctrl, methionine and cystine deficient media (MCDM), MCDM + livogrit, MCDM + pioglitazone | 72 | GSH, mean ± standard deviation (µmol/L): MCDM: 3.05 ± 0.14 MCDM + livogrit: 4.82 ± 0.13 MCDM + pioglitazone: 3.73 ± 0.01 | GSH, mean ± standard deviation (µmol/L): 7.83 ± 1.26 | Fluorimetric | GSH: - Lower in MCDM vs. Ctrl (p < 0.01) -Recovery with livogrit at higher doses (p < 0.001) and pioglitazone (p < 0.05) | [172] |
L02 cells | Ctrl, cholesterol (CHO) | 24 | nr | nr | Enzymatic recycling | GSSG/GSH Higher in CHO vs. respective Ctrl (p < 0.05) | [173] |
HepG2 cells | Ctrl, 0.55 mM fructose (FC1), 1 mM fructose (FC2), 1 mM fructose + 0.1 µM insulin (FC3) | 48 | nr | nr | Ellman | GSH: Lower in FC1 and FC2 vs. Ctrl (p < 0.05) | [174] |
AML12 cells | Ctrl, PA | 24 | nr | nr | High-performance liquid chromatography-mass spectrometry (HPLC-MS) | GSH: Lower in palmitate vs. Ctrl (p < 0.05) | [144] |
L02 cells | Ctrl, FFAs, FFAs + peonidin 3-O-glucoside (P3G) | 24 | nr | nr | Fluorimetric | GSH: Lower in FFAs vs. Ctrl and vs. treatment at the higher dose (p < 0.01) | [175] |
HepG2 cells | Ctrl, FFAs, FFAs + zeaxanthin (ZEA), FFAs + Fer-1 | 24 | nr | nr | Ellman | GSH: - Lower in FFAs vs. Ctrl (p < 0.05) and vs. FFAs + Fer-1 group - Recovery in all treatment groups | [176] |
AML12 and HepG2 cells | Ctrl, FFAs, erastin (E), Fer-1 | 24 | nr | nr | Ellman | GSH: Lower in FFAs and E vs. Ctrl (p < 0.01) | [147] |
HepG2 cells | Ctrl, FFAs, FFAs + sulphasalazine (SAS), FFAs + melatonin (MEL) | nr | nr | nr | Ellman | GSH: Lower in FFAs and SAS vs. Ctrl (p < 0.0001) Recovery with the higher dose of MEL (p < 0.0001) | [148] |
HepG2 cells | 40% fetal bovine serum (FBS), FBS + FENO, FBS + S2 compound | 48 | nr | nr | Enzymatic recycling | GSH/GSSG and GSH: Lower in FBS vs. Ctrl and vs. treatments (p < 0.05) | [92] |
HepG2 cells | Ctrl, FFAs, FFAs + arbutin (ARB) | 24 | nr | nr | Ellman | GSH: Lower in FFAs vs. FFAs + ARB (p < 0.05) | [151] |
HepG2 cells | Ctrl, FFAs, FFAs + ALA | 24 | nr | nr | HPLC-UV | GSH: - Lower in FFAs vs. Ctrl (p < 0.01) - Recovery with all treatments (p < 0.05, p < 0.01) | [177] |
HepG2 cells | Ctrl, FFAs, FFAs + MC3482 compound | nr | nr | HPLC-UV | GSH: Lower in FFAs vs. Ctrl and vs. FFAs + MC3482 (p < 0.0001) | [178] |
Model | Diet/Supplements | Length of Study (Weeks) | Thiol Levels in MASLD Model | Thiol Levels in Normal Diet (ND) | Method | p-Values | Ref. |
---|---|---|---|---|---|---|---|
C57BL/6 mice | ND, methionine, and choline-deficient (MCD) diet, ND + PCB-126, MCD + PCB-126 | 14 | Not reported (nr) | nr | High-performance liquid chromatography-mass spectrometry (HPLC-MS) | Hepatic CysGly and Cys: - No significance between MCD vs. ND - Higher in MCD vs. MCD + PCB126 group (p < 0.05) | [110] |
C57BL/6J mice | ND, high-fat diet (HFD) | 14 | Hepatic homocysteine (median, interquartile range): HFD: 2.3 (2.1–2.7) μM/100 mg; | Hepatic homocysteine (median and interquartile range): ND: 2.4 (2.1–2.9) μM/100 mg | HPLC-MS | No significance between HFD and ND | [179] |
nr | ND, high-fat and high-fructose diet (HFHF), HFHF + lupeol (L), HFHF + MET | 8 | Hepatic free thiols, mean ± standard deviation (nmol/mg protein): HFHF: 0.28 ± 0.02 HFHF + L: 3.6 ± 0.10 HFHF + MET: 3.3 ± 0.20 | Hepatic thiols, mean ± standard deviation (nmol/mg protein): ND: 3.9 ± 0.30 | Ellman | - Lower in HFHF vs. ND (p < 0.05) - Recovery with treatments (p < 0.05) | [180] |
Age | Study Type | Patient Number | LMW Thiols | Method | p-Value | Ref. |
---|---|---|---|---|---|---|
Adults | Prospective observational (case-control) | Controls: 40 Patients with early MASLD: 29 Patients with advanced MASLD: 38 | Plasma GSH, median, interquartile range (mg/mg protein): Control: 0.79 (0.67–1.28) Early MASLD: 1.37 (1.07–2.25) Advanced MASLD: 1.66 (1.08–2.02) | Ellman | Higher in early and advanced MASLD vs. controls (p < 0.001) | [182] |
Adults | Retrospective, observational (population-based cohort) | FLI < 60: 3911 FLI ≥ 60: 1651 | Free thiols, mean ± standard deviation (µmol/L/g protein): FLI < 60: 5.05 ± 0.99 FLI ≥ 60: 4.91 ± 1.02 | Ellman | Significance between FLI > 60 and FLI < 60 estimated through multivariable logistic regression analyses (p < 0.001) | [183] |
Adults | Prospective observational (case-control) | Controls: 69 MASLD: 144 | nr | Gas chromatography-mass spectrometry | Blood GSH: Lower in MASLD vs. controls (p < 0.001) | [184] |
Adults | Prospective observational (cross-sectional) | Controls: 25 MASLD: 60 | Free thiols, mean ± standard deviation (µmol/L) Control: 11.70 ± 0.33 MASLD: 10.61 ± 0.13 | Ellman | Lower in MASLD vs. controls (p < 0.05) | [185] |
Children | Retrospective observational (longitudinal: Baseline (T0) and 12-month follow-up (T1)) | MASLD: 24 | Plasma tGSH, median, interquartile range (μmol/L): T0: 26.0 (20.5–38.5) T1: 31.5 (25.5–38.5) Plasma Hcy, mean, standard deviation (μmol/L): T0: 15.7 ± 4.1 T1: 21.1 ± 9.3 | High-performance liquid chromatography-fluorescence detector (HPLC-FD) | Plasma tGSH: ns Plasma Hcy: Lower in T0 vs. T1 (p < 0.05) | [186] |
Adults | Prospective observational (case-control) | Controls: 8 MASLD: 6 | nr | Fluorimetric | Peripheral mononuclear cells GSH: Lower in MASLD vs. control (p < 0.05) | [187] |
Age | Study Design | Patient Number | GSH Levels in the Placebo Group | GSH Levels in the Treatment Group | Method | p-Value | Ref. |
---|---|---|---|---|---|---|---|
Children | - Randomized, double-blind placebo-controlled trial. - Two arms: the arm of placebo (PLA); and the arm of treatment with hydroxytyrosol and vitamin E (HXTE). - Time: Baseline (T0) and 4-month follow-up (T1). | PLA: 40 HXTE: 40 | Plasma GSH, mean ± standard deviation (μM): T0: 29.6 ± 51.8 T1: 52.2 ± 85.0 Plasma GSSG, mean ± standard deviation (μM): T0: 1.5 ± 2.3 T1: 4.0 ± 4.9 Plasma GSH/GSSG, mean ± standard deviation: T0: 40.8 ± 61.1 T1: 132.9 ± 108.7 | Plasma GSH, mean ± standard deviation (μM): T0: 47.1 ± 13.0 T1: 101.8 ± 43.8 Plasma GSSG, mean ± standard deviation (μM): T0: 1.9 ± 0.9 T1: 4.9 ± 2.8 Plasma GSSG/GSH, mean ± standard deviation: T0: 77.7 ± 80 T1: 189.5 ± 121.0 | High-performance liquid chromatography (HPLC)-UV | GSH and GSH/GSSG: - Higher at T1 vs. T0 in PLA and in HXTE (p < 0.02) GSSG: Higher at T1 vs. T0 in HXTE (p < 0.001) | [188] |
Adults | - Randomized, double-blind, placebo-controlled trial. - Three arms: the arm of PLA; the arm of treatment with a low dose of pinitol (P300 mg); and the arm with a high dose of pinitol (P500 mg). - Time: Baseline (T0) and 12-week follow-up (T1). | PLA: 30 P300: 30 P500: 30 | Serum GSH, mean ± standard deviation (μM): T0: 198.3 ± 37.8 T1: 217.6 ± 37.8 | Serum GSH, mean ± standard deviation (μM): P300 (T0): 248.9 ± 38.3 P300 (T1): 273.8 ± 39.8 P500 (T0): 158.0 ± 28.4 P500 (T1): 186.7 ± 28.8 | Ellman | Not significant (ns) | [189] |
Adults | - Open-label, parallel-group, randomized–controlled trial. - Two arms: the arm of standard management therapy (SMT); and the arm of treatment with SMT plus H. pylori-eradication therapy (HPET). - Time: Baseline (T0) and 24-week follow-up (T1). | SMT: 28 HPET: 36 | – | Serum GSH, median, interquartile range (µg/mL): SMT (T0): 192.4 (151.4–213.1) SMT (T1): 196.7 (181.0–213.7) HPET (T0): 159.0 (143.2–183.1) HPET (T1): 188.5 (167.4–221.3) | Ellman | Higher at T1 vs. T0 in HPET (p < 0.05) | [190] |
Children | - Randomized, crossover, one-side open trial. - Two arms: the arm of calorie-restricted regimen (RCR); and the arm of RCR plus supplement of lycopene-rich tomato juice (RCRT). - Time: Baseline (T0), 60-day crossover (T1), 60-day follow-up (T2). | RCR: 27 RCRT: 34 | Not reported (nr) | nr | Enzymatic recycling | Serum GSH/GSSG and GSH: Higher in RCR and RCRT at T2 vs. T0 (p < 0.01) Blood GSSG: Lower in RCRT at T1 and T2 vs. T0 (p < 0.01) | [191] |
Adults | - Randomized, double-blinded, placebo-controlled trial. - Two arms: the arm of PLA; the arm of treatment with VSL#3® (VSL#3). - Time: Baseline (T0) and 10-week follow-up (T1). | PLA: 16 VSL#3: 19 | Blood GSH/GSSG: T0: 20 ± 12 T1: 21 ± 9 | Blood GSH/GSSG: T0: 22 ± 10 T1: 26 ± 13 | Enzymatic recycling | ns | [192] |
Children | - Single-blind, randomized, controlled, parallel dietary intervention. - Two arms: the arm with low-fat diet (LFD); and the arm of treatment with Mediterranean diet (MD). - Time: Baseline (T0) and 12-week follow-up (T1). | LFD: 22 MD: 22 | – | Blood GSH, mean ± standard deviation (mg/L): LFD (T0): 82.0 ± 118.10 LFD (T1): 81.5 ± 100.68 MD (T0): 62.5 ± 97.53 MD (T1): 87.0 ± 39.29 | Ellman | Higher in the MD group compared to LFD at T1 (p < 0.05) | [193] |
Adults | - Clinical study with a single arm. - The arm of treatment with pioglitazone. - Time: Baseline (T0) and 3-month follow-up (T1). | MASLD: 37 | – | Serum Thiols, mean ± standard deviation (µmol/L): T0: 181.26 ± 59.92 T1: 182.44 ± 54.06 | Ellman | Higher in T1 vs. T0 (p < 0.015) | [194] |
Adults | - Clinical study with a single arm. - Retrospective analysis based on the adherence to MD: low adherence (LA) group; high adherence (HA) group. - Time: Baseline (T0) and 24-month follow-up (T1). | LA: 20 HA: 20 | – | GSH, mean ± standard deviation (mmol/109 erythrocytes) LA (T0): 5.8 ± 2.7 LA (T1): 6.8 ± 1.9 HA (T0): 6.0 ± 2.3 HA (T1): 8.5 ± 3.2 | Ellman | Higher in HA at T1 vs. T0 (p < 0.05); and HA at T1 vs. LA at T1 (p < 0.05) | [195] |
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Cesarini, L.; Grignaffini, F.; Alisi, A.; Pastore, A. Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review. Antioxidants 2024, 13, 1461. https://doi.org/10.3390/antiox13121461
Cesarini L, Grignaffini F, Alisi A, Pastore A. Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review. Antioxidants. 2024; 13(12):1461. https://doi.org/10.3390/antiox13121461
Chicago/Turabian StyleCesarini, Lucia, Flavia Grignaffini, Anna Alisi, and Anna Pastore. 2024. "Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review" Antioxidants 13, no. 12: 1461. https://doi.org/10.3390/antiox13121461
APA StyleCesarini, L., Grignaffini, F., Alisi, A., & Pastore, A. (2024). Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review. Antioxidants, 13(12), 1461. https://doi.org/10.3390/antiox13121461