Research Article Details

Article ID: A46231
PMID: 20156580
Source: Int J Biochem Cell Biol
Title: Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro.
Abstract: Nonalcoholic steatohepatitis with fibrosis is a more severe form of nonalcoholic fatty liver disease, one of the most common liver diseases. We have previously shown that peroxisome proliferator-activated receptors gamma (PPARgamma) ligand, rosiglitazone, prevented the development of the methionine choline deficient (MCD) diet-induced fibrosing steatohepatitis. We have now tested whether overexpression of PPARgamma ameliorates established steatohepatitis and fibrosis. Male C57BL6 mice fed with MCD diet for 8 weeks developed hepatic fibrosis with increased hepatic expression of collagen1alpha(I), inhibitors of fibrosis reversal-1, regulator involved in matrix degradation-9 and connective tissue growth factor. After 2 weeks of transduction of PPARgamma through an adenovirus-expressing PPARgamma (Ad-PPARgamma), expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells (HSCs) and resolution of liver fibrosis. On the in vitro study, PPARgamma is expressed in primary quiescent HSC, but depleted in culture activated HSC. Conversely, ectopic expression of PPARgamma in activated HSC achieved the phenotypic reversal to the quiescent cell. Such induction markedly suppressed cell viability and cell proliferation, downregulated proliferating cell nuclear antigen, and caused cell cycle arrest at G0/G1 phase. Further, introduction of PPARgamma in HSC increased cell apoptosis, this was confirmed by enhanced expression of FasL, cleaved caspase-3, cleaved caspase-7 and poly ADP-ribose polymerase, indicating an extrinsic apoptosis pathway. In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by overexpression of PPARgamma. It is likely that PPARgamma reverses fibrosis by reducing HSCs proliferation, inducing cell cycle arrest and apoptosis.
DOI: 10.1016/j.biocel.2010.02.006

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S17 Genetic therapy Genetic approaches; genetherapy; Gene therapy HSD17B13 inhibitor; PNPLA3-rs7 38409 (I148M) variant inhibitor; PNPLA3 expression down-regulator INI-678; Momelotinib 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
S13 Anti-apoptosis hepatocyte apoptosis; hepatic autophagy; apoptosis Pan-caspase inhibitor Emricasan Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T05 Peroxisome proliferator-activated receptor gamma PPARG agonist Nuclear hormone receptor P37231 PPARG_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T11 Caspase-3 CASP3 inhibitor Enzyme P42574 CASP3_HUMAN Details
T12 Caspase-7 CASP7 inhibitor Enzyme P55210 CASP7_HUMAN Details
T20 Fatty acid synthase FASN inhibitor Enzyme P49327 FAS_HUMAN Details

Diseases ID DO ID Disease Name Definition Class

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D075 Choline Supplement DB00122 PLD2 product of; PLD1 product of -- Under clinical trials Details
D311 Rosiglitazone Chemical drug DB00412 PPARG agonist; PPARA; PPARD Improve insulin resistance Failed in clinical trials Details