Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease
Objective: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods:...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/85541 http://hdl.handle.net/10220/45208 |
| _version_ | 1826121119024807936 |
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| author | Mohammad Zarei Barroso, Emma Palomer, Xavier Dai, Jianli Rada, Patricia Quesada-López, Tania Escolà-Gil, Joan Carles Cedó, Lidia Mohammad Reza Zali Molaei, Mahsa Dabiri, Reza Vázquez, Santiago Pujol, Eugènia Valverde, Ángela M. Villarroya, Francesc Liu, Yong Wahli, Walter Vázquez-Carrera, Manuel |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Mohammad Zarei Barroso, Emma Palomer, Xavier Dai, Jianli Rada, Patricia Quesada-López, Tania Escolà-Gil, Joan Carles Cedó, Lidia Mohammad Reza Zali Molaei, Mahsa Dabiri, Reza Vázquez, Santiago Pujol, Eugènia Valverde, Ángela M. Villarroya, Francesc Liu, Yong Wahli, Walter Vázquez-Carrera, Manuel |
| author_sort | Mohammad Zarei |
| collection | NTU |
| description | Objective: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods: Studies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Results: Increased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Conclusions: Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development. |
| first_indexed | 2024-10-01T05:27:31Z |
| format | Journal Article |
| id | ntu-10356/85541 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:27:31Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/855412020-11-01T05:20:52Z Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease Mohammad Zarei Barroso, Emma Palomer, Xavier Dai, Jianli Rada, Patricia Quesada-López, Tania Escolà-Gil, Joan Carles Cedó, Lidia Mohammad Reza Zali Molaei, Mahsa Dabiri, Reza Vázquez, Santiago Pujol, Eugènia Valverde, Ángela M. Villarroya, Francesc Liu, Yong Wahli, Walter Vázquez-Carrera, Manuel Lee Kong Chian School of Medicine (LKCMedicine) VLDLR PPAR Objective: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods: Studies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Results: Increased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Conclusions: Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development. Published version 2018-07-24T08:13:54Z 2019-12-06T16:05:39Z 2018-07-24T08:13:54Z 2019-12-06T16:05:39Z 2017 Journal Article Mohammad Zarei, Barroso, E., Palomer, X., Dai, J., Rada, P., Quesada-López, T., et al. (2018). Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease. Molecular Metabolism, 8, 117-131. 2212-8778 https://hdl.handle.net/10356/85541 http://hdl.handle.net/10220/45208 10.1016/j.molmet.2017.12.008 en Molecular Metabolism © 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 15 p. application/pdf |
| spellingShingle | VLDLR PPAR Mohammad Zarei Barroso, Emma Palomer, Xavier Dai, Jianli Rada, Patricia Quesada-López, Tania Escolà-Gil, Joan Carles Cedó, Lidia Mohammad Reza Zali Molaei, Mahsa Dabiri, Reza Vázquez, Santiago Pujol, Eugènia Valverde, Ángela M. Villarroya, Francesc Liu, Yong Wahli, Walter Vázquez-Carrera, Manuel Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title | Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title_full | Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title_fullStr | Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title_full_unstemmed | Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title_short | Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease |
| title_sort | hepatic regulation of vldl receptor by pparβ δ and fgf21 modulates non alcoholic fatty liver disease |
| topic | VLDLR PPAR |
| url | https://hdl.handle.net/10356/85541 http://hdl.handle.net/10220/45208 |
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