PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells.
Details
Serval ID
serval:BIB_1C8038E5F6C1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells.
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN
1950-6007 (Electronic)
ISSN-L
0753-3322
Publication state
Published
Issued date
10/2024
Peer-reviewed
Oui
Volume
179
Pages
117303
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard <sup>-/-</sup> mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.
Keywords
Hepatic Stellate Cells/metabolism, Hepatic Stellate Cells/drug effects, Hepatic Stellate Cells/pathology, Animals, Phosphorylation/drug effects, PPAR-beta/agonists, PPAR-beta/metabolism, PPAR-beta/genetics, Liver Cirrhosis/metabolism, Liver Cirrhosis/pathology, PPAR delta/metabolism, PPAR delta/agonists, PPAR delta/genetics, Smad3 Protein/metabolism, AMP-Activated Protein Kinases/metabolism, Mice, Inbred C57BL, E1A-Associated p300 Protein/metabolism, Male, Mice, Humans, Thiazoles/pharmacology, Diet, High-Fat/adverse effects, Mice, Knockout, Insulin Resistance, Cell Line, Transforming Growth Factor beta1/metabolism, AMPK, ERK1/2, Fibrosis, LX-2, P300, PPARβ/δ
Pubmed
Web of science
Open Access
Yes
Create date
26/08/2024 11:48
Last modification date
01/10/2024 7:11