Research Article Details
| Article ID: | A21857 |
| PMID: | 24995693 |
| Source: | Hepatology |
| Title: | The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. |
| Abstract: | UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. CONCLUSION: The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression. |
| DOI: | 10.1002/hep.27297 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T03 | Peroxisome proliferator-activated receptor alpha | PPARA | agonist | Nuclear hormone receptor | Q07869 | PPARA_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |