Research Article Details
| Article ID: | A24201 |
| PMID: | 23127227 |
| Source: | Clin Exp Pharmacol Physiol |
| Title: | Thiazolidinediones improve hepatic fibrosis in rats with non-alcoholic steatohepatitis by activating the adenosine monophosphate-activated protein kinase signalling pathway. |
| Abstract: | Thiazolidinediones (TZDs) markedly reduce hepatic steatosis in both rodents and humans. However, the effects and mechanisms of action of TZDs on hepatic fibrosis remain unclear. The aim of the present study was to determine the effects of TZDs on histological changes in the liver and on the modulation by adiponectin via the AMP-activated protein kinase (AMPK) signalling pathway in rats with non-alcoholic steatohepatitis (NASH). Forty rats were divided into normal control, high-fat diet (HFD), pioglitazone control and pioglitazone intervention groups. After 24 weeks treatment with pioglitazone (10 mg/kg per day by gavage), changes in liver histology, serum aminotransaminase, triglyceride (TG), free fatty acid (FFA), glucose, insulin, adiponectin and transforming growth factor (TGF)-β1 concentrations and hepatic adiponectin, AMPK, α-smooth muscle actin (α-SMA) and collagen I expression were evaluated. The degree of hepatic steatosis and fibrosis was significantly higher in HFD-induced NASH rats compared with normal controls, as were serum concentrations of aminotransaminase, TG, FFA, glucose, insulin and TGF-β1 and hepatic expression of α-SMA and collagen I protein. Serum adiponectin concentrations and hepatic expression of adiponectin mRNA and AMPK protein were significantly lower in the HFD-induced NASH rats compared with the normal control. Pioglitazone significantly reduced the degree of hepatic steatosis and fibrosis, as well as serum concentrations of aminotransaminase, TG, FFA, glucose, insulin and TGF-β1 and hepatic expression of α-SMA and collagen I protein. In addition, pioglitazone significantly increased serum adiponectin concentrations and hepatic expression of adiponectin mRNA and AMPK protein. In conclusion, the TZD pioglitazone improved hepatic fibrosis in rats with NASH by upregulating adiponectin expression and activating AMPK, thus subsequently inhibiting the activation of hepatic stellate cells and the overproduction of extracellular matrix. |
| DOI: | 10.1111/1440-1681.12020 |
| 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 |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D366 | Thiazolidinediones | Chemical drug | DB11898 | -- | -- | Under clinical trials | Details |
| D275 | Pioglitazone | Chemical drug | DB01132 | PPARG agonist | Improve insulin resistance | Advanced in clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |