Research Article Details
| Article ID: | A47327 |
| PMID: | 16958658 |
| Source: | J Gastroenterol Hepatol |
| Title: | Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. |
| Abstract: | Cirrhosis is the most important consequence of alcoholic liver disease for which liver transplantation is the only treatment option available. Transdifferentiation of hepatic stellate cells (HSC) to myofibroblastic cells (MF) is a central event in liver fibrogenesis, and understanding molecular mechanisms that underlie this cellular event provides pivotal insights into development of new therapeutic modalities for cirrhosis. To this end, the authors proposed several years ago that transdifferentiation of quiescent HSC to MF may be causally associated with transcriptional regulation known for adipocyte-preadipocytic fibroblast dedifferentiation. In support of this notion, the authors showed that adipogenic transcription factors and their downstream adipocyte specific genes are expressed abundantly in quiescent HSC and that this expression profile is lost in HM. Further, gain-of-function manipulations for adipogenic transcription factors such as peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and sterol regulatory element binding protein-1c have been shown to reverse culture-induced MF to quiescent HSC. The authors also demonstrated that tumor necrosis factor-alpha and Wnt, known mediators of anti-adipogenesis, also suppress the activity of PPAR-gamma and contribute to HSC-MF transdifferentiation. These results reinforce the concept of adipogenic regulation essential to the quiescent phenotype and the loss of such regulation underlying HSC-HM transdifferentiation. They also provide insights into the molecular basis for the use of PPAR-gamma agonists, which has been advocated for treatment of liver fibrosis. |
| DOI: | 10.1111/j.1440-1746.2006.04573.x |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S10 | Liver transplantation | -- | -- | -- | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | 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 |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |