1. PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells.
- Author
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Zhang M, Barroso E, Peña L, Rada P, Valverde ÁM, Wahli W, Palomer X, and Vázquez-Carrera M
- Subjects
- Animals, Phosphorylation drug effects, Male, Mice, Humans, Thiazoles pharmacology, Diet, High-Fat adverse effects, Mice, Knockout, Insulin Resistance, Cell Line, Transforming Growth Factor beta1 metabolism, Hepatic Stellate Cells metabolism, Hepatic Stellate Cells drug effects, Hepatic Stellate Cells pathology, 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
- 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
-/- 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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