Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review
Abstract
:1. Introduction
2. Results
2.1. Identified Records
2.2. Altered Circulating Levels of Thyroid Hormone and the Liver
Manuscript | Sample | Study Design | MAFLD Assessment Technique | Groups | Serum Levels of THs | Effect on Liver |
---|---|---|---|---|---|---|
Klieverik et al. [14] (2009) | Rats | — | — | G1: Euthyroid G2: Hypothyroidism G3: Thyrotoxic | G2: ↓ THs G3: ↑ THs | Hypothyroidism ↓ Absorption of FFAs in oxidative tissues ↑ FFAs WAT absorption Thyrotoxic ↑ Absorption of oxidative tissue FFAs |
Liangpunsakul et al. [18] (2003) | Human | Retrospective study | Biopsies and imaging | G1: Control G2: NASH | G2: ↓ T3 | Increased risk to NASH development |
Chung et al. [19] (2012) | Human | Cross sectional | Imaging | G1: Euthyroidism with NAFLD G2: Subclinical hypothyroidism with NAFLD | G2: ↓ T3 | ↑ NAFLD prevalence |
Bano et al. [15] (2016) | Human | Prospective cohort | Imaging | G1: NAFLD Euthyroidism G2: NAFLD Hypothyroidism G3: NAFLD Hyperthyroidism | G2: ↓ THs | ↑ Fibrosis ↑ Risk for NAFLD progression |
Kim et al. [20] (2018) | Human | Cross sectional | Biopsies | G1: NAFLD strict-normal thyroid function G2: NAFLD low thyroid function | G2: ↓ THs | ↑ Fibrosis ↑ Risk of progression to NASH |
Manka et al. [21] (2019) | Human | Retrospective study | Imaging | G1: NAFLD grade 1 G2: NAFLD grade 2 G3: NAFLD grade 3 G4: NAFLD grade 4 | G1: ↓ T3 G2: ↓↓ T3 G3: ↓↓ T3 G4: ↓↓↓ T3 | ↑ Risk of Fibrosis |
Kim et al. [22] (2020) | Human | Retrospective study | Imaging | G1: NAFLD strict-normal thyroid function G2: NAFLD low thyroid function | G2: ↓ THs | ↑ Fibrosis ↑ Risk for all-cause and cardiovascular mortality |
D’Ambrosio et al. [23] (2021) | Human | Retrospective Single-Center study | Biopsies | G1: NASH G2: Fibrosis G3: Steatosis | G1: ↓ T3 G2: ↓↓ T3 G3: ↓↓↓ T3 | ↑ Risk of NAFLD progression |
Du et al. [16] (2021) | Human | Retrospective study | Imaging | G1: DM2 with NAFLD without Fibrosis G2: DM2 + NAFLD + Fibrosis | G2: ↓ T3 | ↑ Fibrosis |
Chaves et al. [17] (2021) | Human | Cross sectional | Imaging | G1: R243Q mutation of the THR-β gene G2: Their wild-type first-degree relatives | G1: ↓ THR-β | ↑ Risk for NAFLD progression |
Wang et al. [24] (2021) | Human | Cross sectional | Imaging | G1: Hypothyroidism G2: Hypothyroidism + NAFLD | G2: ↓ T3 | ↑ Liver FFAs |
2.3. Metabolic Action of Thyroid Hormone in Liver with MAFLD
Manuscript | Sample | Study Design | NAFLD Assessment Technique | Groups | Treatment | Dose | THs | TH Target | Effect on Liver |
---|---|---|---|---|---|---|---|---|---|
Mustafa et al. [25] (2009) | Human | Cross sectional | Imaging | G1: Control G2: NASH | — | — | G2: ↓ T3 | ↑ serum MDA ↑ serum NO ↓ serum GSH ↓ serum GPx | ↑ Risk NASH progression |
Krause et al. [26] (2018) | Human | Cohort Study | Biopsies | G1: NAFLD | — | — | G1: ↓ T3 | ↓ Dio1 mRNA ↓ THR-β mRNA | ↑ Hyperlipidemia ↑ Risk NASH progression |
Harrison et al. [27] (2019) | Human | Randomized Controlled Trial | Biopsies | G1: NASH + Placebo G2: NASH + MGL-3196 | MGL-3196 | 80 mg | G2: ↑ THR-β | THR-β | ↓ Hepatic fat Restoration of Mitochondrial function |
Harrison et al. [28] (2021) | Human | Extension Study | Biopsies | G1: NASH | MGL-3196 | 80 or 100 mg | G1: ↑ T3 and ↓ rT3 | THR-β | ↓ Risk NASH progression |
Manuscript | Sample | Groups | Treatment | Dose | THs | TH Target | Effect on Liver |
---|---|---|---|---|---|---|---|
Nozaki et al. [31] (1992) | Cells | HepG2 cells | T3 | 0.1/μg/mL 0.2/μg/mL 0.3/μg/mL | ↑ T3 | ↑ HTGL mRNA ↑ Hepatic lipid hydrolysis | ↑ Lipogenesis |
Zhang et al. [32] (2004) | Cells | HepG2 cells with Luciferase Vectors-CPT-1 | T3 | 100 nM | ↑ T3 | ↑ PGC-1α mRNA ↑ CPT-1α mRNA | ↑ Fatty acid β-oxidation |
Grasselli et al. [29] (2011) | Cells | G1: Control G2: FFAs G3: FFAs + T2 G4: FFAs + T3 | T2 T3 | 10−7 to 10−5 M 10−7 to 10−5 M | G3: ↑ T2 G4: ↑ T3 | ↓ PPAR-δ and -γ mRNA ↓ SOD ↓ CAT | ↓ Excess fat ↓ TAG |
Grasselli et al. [30] (2014) | Cells | G1: Control cells G2: Hepatoma cell + oleate/palmitate | T2 T3 | 10−6 M to 10−5 M | G2: ↑ T3 | ↑ UCP2 mRNA ↑ CPT-1 mRNA ↑ UCP2 protein ↑ CPT1 protein ↑ ROS ↓ CAT ↓ GSH | ↓ Extracellular TAG ↑ Fatty-acid oxidation ↓ NAFLD progression |
Ness et al. [46] (1990) | Rats | G1: Normal G2: Hypophysectomized | T3 | 10 μg/100 g | G2: ↑ T3 | ↑ CYP7A1 mRNA | ↑ Cholesterol metabolism |
Huang et al. [44] (1998) | Rats | G1: Hypothyroidism G2: Hyperthyroidism G3: Euthyroidism | — | — | G1: ↓ THs G2: ↑ THs | Hyperthyroid ↑ Acetyl-CoA carboxylase mRNA Hypothyroid ↓ Acetyl-CoA carboxylase mRNA | Hyperthyroid ↑ Hepatic lipogenesis Hypothyroidism ↓ Hepatic lipogenesis |
Feng et al. [43] (2000) | Mice | G1: Control G2: Hyperthyroid | — | — | G2: ↑ T3 + THR | ↑ G6PC ↑ PCK1 | ↑ Glycogenolysis ↑ Gluconeogenesis |
Jackson-Hayes et al. [53] (2003) | Mice | Transgenics (CPT-1α-luciferase) with/without the 1st intron of the CPT-1α gene | — | — | ↑ T3 + THR | ↑ CPT-1α gene | ↑ Fatty acid β-oxidation |
Noguchi-Yachide et al. [49] (2007) | Mice | G1: Euthyroidism G2: Thyrotoxic G3: Hypothyroidism | — | — | G2: ↑ T3 + THR | ↑ LXR-α mRNA ↑ CYP7A1 mRNA | Lipid homeostasis |
Liu et al. [52] (2007) | Mice | G1: WT control G2: Mutation in THR | — | — | G2: ↓ T3 + THR | ↓ PPARα protein | ↓ Fatty acid β-oxidation |
Lopez et al. [45] (2007) | Rats | G1: Normal G2: Hypophysectomized G3: Thyroidectomy | T3 | 10 μg/100 g | G3: ↑ T3 | ↑ LDL receptor mRNA | ↑ FFA absorption |
Cable et al. [55] (2009) | Rats | G1: NASH + Vehicle G2: NASH + T3 G3: NASH + MB07811 | MB07811 T3 | 1–50 mg/kg/day 650 μg/kg/day | G2: ↑ T3 G3: ↑ T3 + THR | ↑ CPT-1 mRNA ↑ PGC-1α mRNA | ↑ Mitochondrial β-oxidation |
Mollica et al. [38] (2009) | Rats | G1: Control G2: HFD G3: HFD + T2 | T2 | 25 μg/100 g | G3: ↑ T2 | ↑ PPAR-α ↑ CPT-1 | ↑ mitochondrial respiration ↓ degree of steatosis |
Adams et al. [50] (2010) | Mice | G1: C57BL/6 control G2: C57BL/6 with T3 | PBS T3 | 500 μg/kg | G2: ↑ T3 | ↑ FGF21 mRNA | ↑ lipolysis ↑ hepatic fatty acid oxidation |
Sousa et al. [48] (2011) | Rats | G1: Euthyroidism G2: Hypothyroidism | Soybean oil Fish oil | 0.5 mL | G2: ↓ T3 | ↑ PPARα protein ↓ D1 mRNA | ↓ Serum triglycerides ↓ Hepatic TAG levels |
Grasselli et al. [34] (2012) | Rats | G1: DP G2: HFD G3: HFD + T2 G4: DP + T2 | T2 | 25 μg/100 g | G3: ↑ T2 G4: ↑ T2 | ↑ PPARγ mRNA ↑ acyl-CoA oxidase mRNA | ↓ Inflammation ↓ Adipose triglyceride lipase ↑ FFA oxidation |
Santana-Farré et al. [47] (2012) | Rats | G1: Neonatal Hypothyroidism G2: Age-matched euthyroid G3: Euthyroid weight paired | — | — | G1: ↓ T3 | ↑ PPARα mRNA ↓ LXR mRNA ↓ CD36 mRNA ↓ genes uptake Ags | ↓ Absorption of FFAs in the liver |
Cavallo et al. [42] (2013) | Rats | G1: Euthyroid G2: Hypothyroid G3: Hypothyroid + T2 | T2 | 150 µg/100 g | G3: ↑ T2 | ↑ CPT-1 protein ↑ OXPHOS | ↑ Fatty acid β-oxidation ↓ Adiposity ↓ Dyslipidemia |
Alonso-Merino et al. [51] (2016) | Cells Rats | G1: Euthyroid G2: Hyperthyroid | T4 T3 | T4 7 ng/g T3 35 ng/g | G2: ↑ T3 + THR | ↓ TGF-β mRNA | ↓ Fibrosis progression |
Iannucci et al. [35] (2017) | Rats | G1: Control G2: HFD G3: HFD + T2 G4: HFD + T3 | T2 T3 | 25 µg/100 g 2.5 µg/100 g | G3: ↑ T3 + THR G4: ↑ T3 + THR | ↑ CPT-1α protein ↑ UCP2 protein ↑ p-ERK protein ↑ p-Akt protein | ↑ Lipolysis ↑ Autophagy ↑ Fatty acid β-oxidation |
Senese et al. [39] (2017) | Rats | G1: Control G2: HFD G3: HFD + T2 G4: HFD + T3 | T2 T3 | 25 μg/100 g−1 2.5 μg/100 g−1 | G3: ↑ T2 G4: ↑ T3 | ↑ Dio1 mRNA ↑ THRβ mRNA | ↓ TAG ↓ Lipogenesis ↑ Fatty acid oxidation |
Bruinstroop et al. [56] (2018) | Rats | G1: Control G2: MCD diet | — | — | G2: ↓ T3 | ↓ T3 hepatic ↓ Dio1 mRNA | ↑ NAFLD progression |
Xia et al. [40] (2019) | Mice | G1: C57BL/6 control G2: C57BL/6 HFD G3: C57BL/6 HFD + Myr | Myricetin | 100 mg/kg−1 | G3: ↑ T4 and ↑ T3 | ↑ Dio1 mRNA ↑ Dio1 protein ↑ Dio1 activity ↑ THRβ mRNA ↑ THRβ protein | ↓ Hepatic steatosis ↑ Lipid metabolism |
Luong et al. [37] (2020) | Rats | G1: Control G2: HFD G3: HFD + MGL-3169 (5.0 mg/kg) G4: HFD + MGL-3169 (1.5 mg/kg) G5: HFD + MGL-3169 (0.5 mg/kg) G6: HFD + T3 (0.5 mg/kg) | MGL-3196 T3 | 0.5–5.0 mg/kg | G3: ↑ T3 and ↑ THR G4: ↑ T3 and ↑ THR G5: ↑ T3 and ↑ THR G6: ↑ T3 and ↑ THR | ↑ Dio1 mRNA ↑ Me1 mRNA | ↓ Serum lipid profile ↑ FFA oxidation |
Bruinstroop et al. [54] (2021) | Mice | G1: Control NCD G2: Control WDF G3: Dio1 LKD WDF | — | — | G3: ↓ T3 | ↓ Dio1 mRNA ↓ Dio1 activity | ↑ TAG ↑ Cholesterol ↑ Risk for NAFLD progression |
Caddeo et al. [33] (2021) | Mice | G1: C57BL/6 G2: C57BL/6 + HFD G3: C57BL/6 + HFD + MGL-3196 G4: C57BL/6 + HFD + TG68 | MGL-3196 TG68 | 3 mg⋅kg−1 2.8 mg⋅kg−1 | G3: ↑ T3 G4: ↑ T3 | ↑ Dio1 mRNA ↑ THRsp mRNA | ↓ liver weight ↓ Serum TAG ↓ Plasma ALT ↓ Plasma AST |
Kannt et al. [36] (2021) | Mice | G1: C57BL/6J + DP G2: C57BL/6J + HFD G3: C57BL/6J + HFD + Resmetirom | Resmetirom | 3 mg·kg−1 | G3: ↑ THR | ↑ Dio1 mRNA ↑ CYP7A1 mRNA ↑ Me1 mRNA | ↓ Serum lipid profile ↓ Liver weight ↓ NAFLD Score |
Ge et al. [41] (2022) | Mice | G1: C57BL/6 control G2: C57BL/6 LOP G3: C57BL/6 HOP G4: C57BL/6 LOP + Dityr G5: C57BL/6 Dityr | — | — | G2: ↓ T3 G3: ↓ T3 G4: ↓ T3 G5: ↓ T3 | ↓ Dio1 mRNA ↓ THRβ mRNA ↓ CPT-1α mRNA ↓ PPARα mRNA ↓ PGC-1α mRNA ↓ CYP7A1 mRNA ↑ MDA ↑ ROS ↓ CAT ↓ GSH/GSSG | ↑ Risk NAFLD ↑ Inflammation ↑ Oxidative stress ↓ Hepatic energy metabolism ↑ Hepatic lipid synthesis ↓ Hepatic lipid catabolism ↓ Fatty-acid oxidation |
3. Discussion
3.1. THs Dependent Mechanisms in Hepatic Metabolism
3.2. Thyroid Hormone Metabolism Alterations and MAFLD
4. Methods
4.1. Protocol and Registration
4.2. Study Objectives
4.3. Eligibility Criteria
4.4. Search Strategy and Study Selection
4.5. Data Collection and Extraction
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Marschner, R.A.; Arenhardt, F.; Ribeiro, R.T.; Wajner, S.M. Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review. Metabolites 2022, 12, 675. https://doi.org/10.3390/metabo12080675
Marschner RA, Arenhardt F, Ribeiro RT, Wajner SM. Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review. Metabolites. 2022; 12(8):675. https://doi.org/10.3390/metabo12080675
Chicago/Turabian StyleMarschner, Rafael Aguiar, Fernanda Arenhardt, Rafael Teixeira Ribeiro, and Simone Magagnin Wajner. 2022. "Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review" Metabolites 12, no. 8: 675. https://doi.org/10.3390/metabo12080675
APA StyleMarschner, R. A., Arenhardt, F., Ribeiro, R. T., & Wajner, S. M. (2022). Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review. Metabolites, 12(8), 675. https://doi.org/10.3390/metabo12080675