PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells
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, i...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2024
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| Online Access: | https://hdl.handle.net/10356/181357 |
| _version_ | 1826123768273043456 |
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| author | Zhang, Meijian Barroso, Emma Peña, Lucía Rada, Patricia Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Zhang, Meijian Barroso, Emma Peña, Lucía Rada, Patricia Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel |
| author_sort | Zhang, Meijian |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-03-09T13:35:36Z |
| format | Journal Article |
| id | ntu-10356/181357 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-03-09T13:35:36Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1813572024-12-01T15:39:50Z PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells Zhang, Meijian Barroso, Emma Peña, Lucía Rada, Patricia Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences AMPK Fibrosis 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. Published version This study was partly supported by the grants PID2021-122116OBI00 (X.P. and M.V-C.) and PID2021-122766OB-I00 (A.M.V.) funded by MICIU/AEI/10.13039/501100011033 and by “ERDF, A way of making Europe”. CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM) is a Carlos III Health Institute project. We also acknowledge support from the CERCA Programme/Generalitat de Catalunya. E. B is a Serra Hunter fellow. Meijian Zhang was supported by a grant from the China Scholarship Council (CSC) (202007565030). 2024-11-26T06:27:48Z 2024-11-26T06:27:48Z 2024 Journal Article Zhang, M., Barroso, E., Peña, L., Rada, P., Valverde, Á. M., Wahli, W., Palomer, X. & Vázquez-Carrera, M. (2024). PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells. Biomedicine & Pharmacotherapy, 179, 117303-. https://dx.doi.org/10.1016/j.biopha.2024.117303 0753-3322 https://hdl.handle.net/10356/181357 10.1016/j.biopha.2024.117303 39153437 2-s2.0-85201272076 179 117303 en Biomedicine & Pharmacotherapy © 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences AMPK Fibrosis Zhang, Meijian Barroso, Emma Peña, Lucía Rada, Patricia Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title | PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title_full | PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title_fullStr | PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title_full_unstemmed | PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title_short | PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells |
| title_sort | pparβ δ attenuates hepatic fibrosis by reducing smad3 phosphorylation and p300 levels via ampk in hepatic stellate cells |
| topic | Medicine, Health and Life Sciences AMPK Fibrosis |
| url | https://hdl.handle.net/10356/181357 |
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