Vaccinium spp. Berries in the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease: A Comprehensive Update of Preclinical and Clinical Research
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Selection Criteria
2.3. Methodological Quality Assessment
2.4. Study Selection
3. Results
3.1. Overview of Vaccinium spp.
3.2. Study Selection and Characteristics
3.3. Clinical Study
Study | Study Design | Study Population | Type of Intervention | Dose (mg/day) | Trial Duration | ALT Levels (U/L) | AST Levels (U/L) | Insulin (µ/mL) | HOMA IR | Jadad Scale |
---|---|---|---|---|---|---|---|---|---|---|
Hormoznejad et al. 2020 [34] | Randomized double-blind, placebo-controlled clinical trial | Age ≥ 18 years; BMI 25 ± 5 kg/m2, N = 41 (groups: cranberry n = 20, placebo n = 21) | The placebo and cranberry groups received either placebo or cranberry tablets (two tablets; one tablet after lunch and another one after dinner) | 288 | 12 weeks | Before: in the cranberry group: 58.35 ± 18.03; in the placebo group: 55.33 ± 26.10; after: in the cranberry group: 36.90 ± 9.00; in the placebo group: 45.42 ± 15.59 | Before: in the cranberry group: 26.85 ± 10.30; in the placebo group: 29.95 ± 15.02; after: in the cranberry group: 22.60 ± 7.68; in the placebo group: 24.90 ± 15.79 | Before: in the cranberry group: 10.55 ± 1.43; in the placebo group: 10.66 ± 1.55; after: in the cranberry group: 8.20 ± 0.61; in the placebo group: 9.80 ± 1.36 | Before: in the cranberry group: 2.59 ± 0.86; in the placebo group: 2.38 ± 0.71; after: in the cranberry group: 1.88 ± 0.20; in the placebo group: 2.20 ± 0.45 | 5 |
Shirazi et al. 2021 [85] | Randomized double-blind, placebo-controlled clinical trial (parallel) | Age ≥ 18 years, N = 110 (groups: cranberry n = 46, placebo n = 48) | The cranberry capsule includes 144 mg Vaccinium macrocarpon (equal to 13 g dried cranberry fruit) | 144 | 6 months | Before: in the cranberry group: 42.74 ± 15.04; in the placebo group: 47.48 ± 18.35; after: in the cranberry group: 39.54 ± 16.95; in the placebo group: 38.69 ± 14.20 | Before: in the cranberry group: 37.22 ± 13.51; in the placebo group: 41.17 ± 16.69; after: in the cranberry group: 32.98 ± 14.33; in the placebo group: 31.98 ± 12.48 | Before: in the cranberry group: 10.38 ± 3.09; in the placebo group: 10.65 ± 3.02; after: in the cranberry group: 5.62 ± 2.04; in the placebo group: 10.06 ± 2.94 | Before: in the cranberry group: 2.78 ± 0.99; in the placebo group: 2.84 ± 0.98; after: in the cranberry group: 1.39 ± 0.62; in the placebo group: 2.51 ± 0.85 | 5 |
3.4. Preclinical Study
3.4.1. Vaccinium and the Alleviation of Liver Steatosis and Hepatocellular Damage
3.4.2. Vaccinium and the Alleviation of Hepatic Fibrosis
3.4.3. Anti-Inflammatory Effects of Vaccinium
3.4.4. Antioxidant Effects of Vaccinium
3.4.5. Vaccinium, Lipid Metabolism, and NAFLD
Impact of Vaccinium on Peroxisome Proliferator-Activated Receptors (PPARs)
Impact of Vaccinium on Sterol Regulatory Element-Binding Proteins (SREBPs)
Influence of Vaccinium on AMP-Activated Protein Kinase (AMPK)
3.4.6. The Effect of Vaccinium on Glucose Metabolism
Study | Study Types | Type of Intervention | Effects | STAIR | |
---|---|---|---|---|---|
Animal Model | Dosage and Duration | Metabolism/Molecular | |||
Ren, Huang, and Cheng 2014 [75] | Male Sprague Dawley rats (200 to 250 g) | Blueberry juice (15 g/kg, once a day) / 8 weeks | Rats were divided into 2 groups: (1) HFD—50 rats; (2) control group—8 rats | ↓ The degrees of NAFLD and degenerated hepatocytes; ↓ Serum activities of AST and ALT; ↓The ratio of TG/HDL-c; ↑ The mRNA levels of SIRT1, PPAR-α; ↓ The levels of SREBP-1c. | 5 |
Morrison et al. 2015 [72] | Female ApoE 3Leiden mice | 0.1% (w/w) Mirtoselect—standardized Vaccinium myrtillus L. extract (36% anthocyanins)/20 weeks | Mice were divided into 3 treatment groups: (1) HCD; (2) HCD and 0.1% (w/w) Mirtoselect; and (3) Western-type diet without cholesterol supplementation | ↓ The development of hepatic steatosis; ↓ Microvesicular steatosis; ↓ An accumulation of lipids esterified to cholesterol (cholesteryl esters); ↓ The hepatic free cholesterol; ↓ p65-NF-κB activity; Expression of Emr1 or Ccl2—not significant; ↓ Neutrophil infiltration and the expression of two neutrophil chemoattractants—Cxcl1 and Cxcl2; ↓ The pronounced increase in collagen and significantly reduced Col1a1 expression. | 4 |
Glisan et al. 2016 [33] | Male C57BL/6J mice (4 weeks old) | 0.8% CBE—4 g per day (CBE, D13051702) (CBE—macerated sulfite-free dried cranberries)/21 weeks | Mice were divided into 2 treatment groups: (1) HFD (n = 24) and (2) CBE diet (n = 24) for 10 weeks | Blood glucose levels, plasma insulin levels, and HOMA-IR—not significant; ↓ The plasma levels of free fatty acids; ↓ The plasma levels of IL-1β; ↓ The serum levels of ALT levels; ↓ The total lipid droplet area in the liver and the total hepatic lipid area; ↓ The hepatic expression of the NF-κB-dependent proinflammatory genes TNF-α (↓47%) and Cox2 (↓46%); ↓ The hepatic mRNA expression of Il1b (55%) and Ucp2 (57%); ↓ The hepatic mRNA levels of C-C chemokine receptor 2 (Ccr2), the CCL2 receptor expressed on recruited monocytes, by 56% and Ccl3 by 55%; ↓ The hepatic expression of Nlrp3 (43%) and Txnip (30%); ↑ The gene expression of hepatic PPAR-α. ↓ The transcription factor responsible for regulating Txnip expression (24%). | 5 |
Ren et al. 2017 [76] | Male Sprague Dawley rats (6 to 8 weeks old) | 10 mL/kg blueberry juice (1 kg blueberries were thawed, milled, and pressed)/12 weeks | Rats were divided into 2 groups: (1) blueberry juice group (injected with 50 μL/kg saline solution and orally received 10 mL/kg blueberry juice and 10 mL/kg liquid placebo daily); (2) blueberry juice and PPAR-α inhibitor group (injected with 50 μL/kg PPAR-α in saline solution and orally received 10 mL/kg blueberry juice and 10 mL/kg liquid placebo daily) | Blueberry juice: ↓ The serum levels of ALT and AST; ↑ The levels of SOD and GSH; ↓ The serum levels of MDA, TG, TC, and LDL-C increased HDL-C levels; ↑ the mRNA levels of PPAR-α, which reduced the level of SREBP-1c and PNPLA-3. Blueberry juice and PPAR-α inhibitor: ↓ the mRNA levels of SREBP-1c and PNPLA3-α. | 5 |
Shimizu et al. 2019 [84] | Male mice C57BL/6 (6 weeks old) | 1% cranberry powder or 5% cranberry powder (anthocyanin 120 mg/100g and proanthocyanidin 2600 mg/100 g)/8 weeks | Mice were divided into 4 treatment groups: (1) ND, (2) HFD, (3) HFD + 1% cranberry powder, and (4) HFD + 5% cranberry powder | ↓ Body weight and concomitantly triggered hyperphagia; ↓ Oxidative stress and proinflammatory cytokine expression (IL-6); The serum levels of glucose—not significant; ↓ The serum levels of TG; ↓ The serum level of ALT; ↓ The serum level of hepatic mRNA of PPAR-γ and MCP-1. | 4 |
Haga et al. 2019 [74] | Male homozygous leptin receptor-deficient (BKS.Cg-+ Leprdb/+ Leprdb/Jcl; db/db) mice (10 weeks old) | 5% and 10% bilberry fruits extracts (≥36% anthocyanin glycosides)/8 weeks | Mice were divided into 4 treatment groups: (1) ND, (2) HFD + HCD, (3) HFD + HCD + 5% bilberry fruit extracts, and (4) HFD + HCD + 10% bilberry fruit extracts | ↓ Fat accumulation and TG contents in mouse liver; Less fibrosis; ↓ The serum levels of ALT and AST; ↓ The plasma levels of GLU and TC; ↓ Proinflammatory cytokine levels (TNF-α, IL-9, IL-1β, and IFN-γ). | 4 |
Li et al. 2020 [35] | Male Sprague Dawley rats (8 weeks old) | Freeze-dried leaf extract of Vaccinium corymbosum L. (PBL)/8 weeks | Mice were divided into 4 groups: (1) ND; (2) HFD (3) HFD + high dose PBL (H-PBL); (4) HFD + low dose PBL (L-PBL). Rats received: PBL at a dose of 400 mg kg/day (H-PBL group) or 100 mg/kg/day (L-PBL group) or an equal volume of vehicle (0.9% NaCl, ND, and HFD groups) by gavage for 9 weeks | ↓ The hepatic TC, TC, L-LDL, ALT, and AST levels; ↓ The hepatic steatosis and inflammatory infiltration; ↓ The generation of hepatic malondialdehyde (MDA); ↓ The hepatic ROS levels; Protection against hepatic oxidative stress; ↓ pAMPKα, PGC-1α, and SIRT3 proteins in liver; ↑ ERRα, Nrf-1, and Nrf-2 genes in liver. | 5 |
Nakano et al. 2020 [81] | Male mice C57BL/6N (5 weeks old) | 2% bilberry anthocyanin extract powder (Mirtoselect)/18 weeks | Mice were randomly divided into 4 groups: (1) ND group, (2) ND + 2% bilberry anthocyanins, (3) WD group, and (4) WD + 2% bilberry anthocyanins | ↓ Body weight, liver weight, epididymal fat mass, liver-to-body-weight ratio, and hepatic fat mass; ↓ The serum level of AST and ALT; ↓ The serum level of MCP-1; ↓ The serum level of TC; ↓ The serum level of insulin; ↑ Insulin resistance; The serum levels of HDL-c, TG, and glucose—not significantly different; ↑ The level of lactic acid in the gut; ↑ The levels of Nrf-2 and SOD2; ↓ The level of Keap1 and TBARS in the liver. | 5 |
Faheem et al. 2020 [71] | Male albino Wistar rats (12 weeks old) | Cranberry nutraceutical (186c1025) diluted in water (40 mg/mL)/8 weeks | Mice were divided into 5 groups: control group: (1) ND for 8 weeks and received 1 mL/kg distilled water orally thrice weekly; HFCD group: (2) HFCD for 8 weeks and received 1 mL/kg distilled water orally three times weekly; 50/HFCD group: (3) HFCD and cranberry (50 mg/kg/day) orally three times weekly; 100/HFCD group: (4) HFCD and cranberry (100 mg/kg/day) orally three times weekly; treated group: (5) ND and cranberry (100 mg/kg/day) orally three times weekly | ↓ Body weight; ↓ The serum levels of ALT and AST; ↓ The serum levels of TG; ↓ HOMA IR; ↑ SOD and GSH; ↑ ADP levels; ↑ Nrf-2; ↓ The serum level of TNF-α, IL-6, NF-κB, ↓ TGF-β and α-SMA tissue levels; ↓ Reduction of collagen deposition; ↑ IRS-2 expression. | 5 |
Zhao et al. 2021 [78] | Male mice C57BL/6 (6–8 weeks old) | Blueberry-derived exosome-like nanoparticles (BELNs) at 25, 50, or 100 mg/kg/4 weeks | Mice in the 3 HFD groups received intragastric administration of blueberry-derived exosome-like nanoparticles at doses of 25, 50, or 100 mg/kg, administered once every other day | ↓ The serum level of insulin, fasting glucose; ↑ Insulin resistance; ↓ The accumulation of lipid droplets in the liver and the liver weight; ↓ The contents of TC and TG, the levels of ALT and AST, and LDL-C; ↑ The content of HDL-C; ↑ The activities of SOD and GSH; ↓ The content of MDA in the liver; Accelerated the translocation of Nrf-2 from the cytoplasm to nuclei in the liver; ↓ The mRNA levels of FAS and ACC1 in the liver; ↓ The expression of Bcl-2, Bax, and HO-1 in the liver. | 5 |
Hewage et al. 2021 [32] | Male C57BL/6J mice (6 weeks old) | (5% w/w) Manitoba lingonberry Vaccinium vitis-idaea L./freeze-dried berry powder/12 weeks | Mice were divided into 3 groups: (1) control (D12450J) diet, (2) HFD (D12492), or (3) HFD supplemented with (5% w/w) Manitoba lingonberry | ↓ The serum levels of ALT and AST; ↓ The hepatic accumulation of TG and TC; ↓ MDA levels and restored GSH levels; ↓ The hepatic GSSG level and restored GSH/GSSG ratio; ↓ The hepatic ACC-1, SREBP-1c mRNA expression, and the nuclear protein level of SREBP-1c; ↑ The expression of Gclc in the liver; ↓ The serum levels of IL-6, MCP-1, and TNF-α mRNA expression; ↑ pAMPK level and pAMPK/AMPK ratio; ↑ Nuclear Nrf-2 protein level in the liver. | 4 |
Ryyti et al. 2021 [80] | Male C57BL/6N mice (8 weeks old) | 20% w/w air-dried lingonberry Vaccinium vitis-idaea L. powder (900 g of fresh lingonberries were used to produce 100 g of berry powder)/6 weeks | Mice were divided into 3 groups: (1) LFD (10 kcal% fat); (2) HFD (46 kcal% fat); (3) HFD with air-dried lingonberry powder (20% w/w) | ↓ The serum levels of ALT; ↓ The expression of the acute phase inflammatory factors Saa1 and Saa2; ↓ The expression of Cyp46a1; ↑ The expression of hydroxysteroid (17-beta) dehydrogenase 6 (Hsd17b6) and insulin-like growth factor binding protein 2 (Igfbp2); ↓ The expression of genes associated with lipid metabolic process (Mogat1, Plin4), inflammatory/immune response or cell migration (Lcn2, Saa1, Saa2, Cxcl14, Gcp1, S100a10), and cell cycle regulation (Cdkn1a, Tubb2a, Tubb6). | 4 |
Hewage et al. 2022 [31] | Male C57BL/6J mice (6 weeks old) | 5% w/w Manitoba wild lingonberry/12 weeks | Mice were divided into 3 groups: (1) a control diet (D12450J) containing 11% kcal fat, 18% kcal protein, and 71% kcal carbohydrate, or (2) an HFD (D12492) containing 62% kcal fat, 18% kcal protein, and 20% kcal carbohydrate, or (3) an HFD supplemented with (5% w/w) Manitoba wild lingonberry | ↓ The hepatic accumulation of TG and TC; ↓ Notch1 expression in the liver; ↓ Liver NICD1 protein and HES1 mRNA levels; ↓ The expression of SREBP-1c and ACC1; ↑ The hepatic mRNA levels of ACOX1 and CPTIα; ↓ Gene expressions of CD36, DGAT1 and DGAT2. | 3 |
Zhu et al. 2022 [77] | Male C57BL/6 mice (8–10 weeks old) | TEC–blueberry monomers were prepared as 1000 ppb, 800, 600, 400, 200, and 100 ppb with 0.1% formic acid methanol solution/16 weeks | Mice were treated with TEC via gavage at doses of 7.5, 15.0, or 30.0 mg/kg daily for 6 weeks following 10 weeks on a high-fat diet (HFD). To achieve tRF-47 knockdown in vivo, a tRF-47 antagomir (5 μg/mouse in 1.5 mL saline) was injected into the tail vein of NASH mice three times a week for 2 weeks, starting after 9 weeks on the HFD | ↓ The serum levels of ALT, AST and MDA; ↑ The level of autophagy marker LC3B in the liver; ↓ The activation of inflammasomes and TLR4; TEC relies on tRF-47 (tRF-47-58ZZJQJYSWRYVMMV5BO) to promote autophagy and weaken pyroptosis. | 5 |
Sotelo-González et al. 2023 [82] | Male Wistar rats | 10% (w/v) blueberry aqueous extracts/18 weeks | Mice were divided into 3 groups: (1) standard-diet-fed group; (2) HFFD (standard diet added with 20% lard and 18% fructose); (3) HFFD with blueberry beverage | ↓ The serum level of TG; ↓ The accumulation of lipid vacuoles; ↓ The accumulation of saturated, monounsaturated, and polyunsaturated fatty acids; ↓ FAS and ACC expression. | 5 |
3.5. Cell Culture Experiments
Study | Study Types | Effects | |
---|---|---|---|
Model | Dosage and Duration | ||
Liu et al. 2011 [79] | Human hepatocellular cancer cell line (HepG2) | Anthocyanin-rich and phenolic-acid-rich fractions from fresh blueberries (Vaccinium spp.) |
|
Wang et al. 2016 [109] | Human hepatocellular cancer cell line (HepG2) | purified ACNs from wild blueberries (Vaccinium spp.); −10, 20, and 40 µg/mL |
|
Haga et al. 2019 [74] | Alpha mouse liver 12 cells | A 90% ethanolic extract of bilberry fruits (≥36% anthocyanin glycosides) |
|
Li et al. 2020 [35] | Human hepatocellular cancer cell line (HepG2) | Blueberry (Vaccinium corymbosum L.) leaves (PBL);3 doses of PBL at 10 (high), 5 (medium), and 2.5 (low) μg/mL |
|
Zhao et al. 2021 [78] | Human hepatocellular cancer cell line (HepG2) | Blueberry-derived exosome-like nanoparticles (BELNs)—100 µg/mL |
|
Wang et al. 2021 [110] | Human hepatocellular cancer cell line (HepG2) | Blueberry leaves (PBL)—6.25, 12.5, 25 µg/mL for 48 h |
|
Zhu et al. 2022 [77] | Human hepatoma cell line HepG2 | 25, 50, and 75 μM C3Glu, myricetin, myricetin 3-o-galactoside, delphinidin, and blueberry monomers (TEC) |
|
Hewage et al. 2022 [31] | Human hepatoma cells (HepG2, cell line: HB-8065) | 5% w/w Manitoba wild lingonberry |
|
4. Discussion
5. Future Research
6. Strength and Limitations
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Książek, E.; Goluch, Z.; Bochniak, M. Vaccinium spp. Berries in the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease: A Comprehensive Update of Preclinical and Clinical Research. Nutrients 2024, 16, 2940. https://doi.org/10.3390/nu16172940
Książek E, Goluch Z, Bochniak M. Vaccinium spp. Berries in the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease: A Comprehensive Update of Preclinical and Clinical Research. Nutrients. 2024; 16(17):2940. https://doi.org/10.3390/nu16172940
Chicago/Turabian StyleKsiążek, Ewelina, Zuzanna Goluch, and Marta Bochniak. 2024. "Vaccinium spp. Berries in the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease: A Comprehensive Update of Preclinical and Clinical Research" Nutrients 16, no. 17: 2940. https://doi.org/10.3390/nu16172940