Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
Abstract
1. Introduction
2. NAFLD
2.1. Epidemiology
2.2. Etiology
2.2.1. Ethnicity
2.2.2. Genetic Factors
2.2.3. Metabolic Factors
2.2.4. Environmental Factors
2.2.5. Gut Microbiota
2.3. Pathophysiology
2.4. Progression and Associated Diseases
3. Current Therapeutic Strategies for NAFLD
3.1. Lifestyle Modification and Bariatric Surgery
3.1.1. Exercise
3.1.2. Dietary Interventions
3.1.3. Bariatric Surgery
3.2. Pharmacotherapy
3.2.1. Pioglitazone
3.2.2. Vitamin E
3.2.3. Other Current and Emerging Medications
3.2.4. Drugs Targeting Nuclear Receptors
4. PPARs as Promising Targets for the Treatment of NAFLD
4.1. Overview of PPARs
4.1.1. Structure, Tissue Expression, and Mode of Action
4.1.2. PPARs in Glucose and Lipid Metabolism
4.1.3. PPARs in Inflammation and HSC Activation
4.1.4. PPARs in NAFLD
4.2. Available PPAR Agonists
4.2.1. PPARα Agonists
4.2.2. PPARβ/δ Agonists
4.2.3. PPARγ Agonists
4.3. Novel PPAR Agonists
4.3.1. Pemafibrate
4.3.2. PPARα and β/δ Dual Agonist Elafibranor
4.3.3. PPARα and γ Dual Agonist Saroglitazar
4.3.4. Pan-PPAR Agonist Lanifibranor
5. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
References
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Isotypes | PPARα | PPARβ/δ | PPARγ |
---|---|---|---|
Main tissue expression | Liver | Skeletal & cardiac muscles | WAT |
Skeletal muscles | BAT | ||
Heart | Liver | Macrophages | |
Kidney | WAT | ||
BAT | BAT | ||
Intestine | Macrophages | ||
Main natural ligands | FA | FA | FA |
Eicosanoids | VLDL components | Arachidonic acid metabolites | |
Phospholipids | |||
Main synthetic single agonists | Fenofibrate | GW501516 | Pioglitazone |
Wy14643 | GW0742 | Rosiglitazone | |
Gemfibrazil | Seladelpar | ||
Pemafibrate | |||
Biological functions related to NAFLD | TG hydrolysis | Muscle FA storage | Adipogenesis |
FA catabolism | FA catabolism | Adipose FA storage | |
Ketogenesis | Lipoprotein metabolism | Adipokine secretion | |
FGF21 production | Glucose utilization | Anti-inflammatory | |
Glycerol metabolism | Anti-inflammatory | Anti-fibrotic | |
Anti-Inflammatory | |||
Potential therapeutic target for | Hypertriglyceridemia | Atherogenic dyslipidemia | Insulin resistance |
Atherogenic dyslipidemia | Insulin resistance | Obesity | |
NAFLD | Obesity | T2DM | |
T2DM | NAFLD | ||
NAFLD |
Compounds | Chemical Structure | Description |
---|---|---|
Pemafibrate | Selective and potent PPARα modulator | |
Clinical application for dyslipidemia | ||
Safety profile in clinical studies | ||
Currently in phase 3: effect on CV events in T2DM | ||
Elafibranor | High activity on PPARα, moderate activity on PPARβ/δ | |
Safety profile in clinical studies | ||
Currently in phase 3: effect on fibrosis in NASH | ||
Saroglitazar | High activity on PPARα, moderate activity on PPARγ | |
Clinical application for dyslipidemia | ||
Safety profile in clinical studies | ||
Currently in phase 2: effect on NAFLD/NASH, phase 3: effect on fibrosis compared to pioglitazone and vitamin E | ||
Lanifibranor | Moderate and balanced activity on PPARα, PPARβ/δ, PPARγ | |
Currently in phase 2: effect on NAFLD/NASH |
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Fougerat, A.; Montagner, A.; Loiseau, N.; Guillou, H.; Wahli, W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020, 9, 1638. https://doi.org/10.3390/cells9071638
Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells. 2020; 9(7):1638. https://doi.org/10.3390/cells9071638
Chicago/Turabian StyleFougerat, Anne, Alexandra Montagner, Nicolas Loiseau, Hervé Guillou, and Walter Wahli. 2020. "Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease" Cells 9, no. 7: 1638. https://doi.org/10.3390/cells9071638
APA StyleFougerat, A., Montagner, A., Loiseau, N., Guillou, H., & Wahli, W. (2020). Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells, 9(7), 1638. https://doi.org/10.3390/cells9071638