PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells

Biomed Pharmacother. 2024 Oct:179:117303. doi: 10.1016/j.biopha.2024.117303. Epub 2024 Aug 18.

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.

Keywords: AMPK; ERK1/2; Fibrosis; LX-2; P300; PPARβ/δ.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Animals
  • Cell Line
  • Diet, High-Fat / adverse effects
  • E1A-Associated p300 Protein* / metabolism
  • Hepatic Stellate Cells* / drug effects
  • Hepatic Stellate Cells* / metabolism
  • Hepatic Stellate Cells* / pathology
  • Humans
  • Insulin Resistance
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Mice, Knockout
  • PPAR delta* / agonists
  • PPAR delta* / genetics
  • PPAR delta* / metabolism
  • PPAR-beta* / agonists
  • PPAR-beta* / genetics
  • PPAR-beta* / metabolism
  • Phosphorylation / drug effects
  • Smad3 Protein* / metabolism
  • Thiazoles / pharmacology
  • Transforming Growth Factor beta1 / metabolism

Substances

  • PPAR-beta
  • PPAR delta
  • GW 501516
  • Smad3 Protein
  • AMP-Activated Protein Kinases
  • E1A-Associated p300 Protein
  • Thiazoles
  • Ep300 protein, mouse
  • Smad3 protein, mouse
  • Transforming Growth Factor beta1