Selective deletion of PPARβ/δ in fibroblasts causes dermal fibrosis by attenuated LRG1 expression

Ming Keat Sng; Jeremy Soon Kiat Chan; Ziqiang Teo; Terri Phua; Eddie Han Pin Tan; Jonathan Wei Kiat Wee; Nikki Jun Ning Koh; Chek Kun Tan; Jia Peng Chen; Mintu Pal; Benny Meng Kiat Tong; Ya Lin Tnay; Xuan Rui Ng; Pengcheng Zhu; Shunsuke Chiba; Xiaomeng Wang; Walter Wahli; Nguan Soon Tan

doi:10.1038/s41421-018-0014-5

Selective deletion of PPARβ/δ in fibroblasts causes dermal fibrosis by attenuated LRG1 expression

Cell Discov. 2018 Apr 3:4:15. doi: 10.1038/s41421-018-0014-5. eCollection 2018.

Authors

Ming Keat Sng^{1

2}, Jeremy Soon Kiat Chan¹, Ziqiang Teo¹, Terri Phua^{1

3}, Eddie Han Pin Tan¹, Jonathan Wei Kiat Wee¹, Nikki Jun Ning Koh¹, Chek Kun Tan², Jia Peng Chen², Mintu Pal⁴, Benny Meng Kiat Tong⁵, Ya Lin Tnay⁵, Xuan Rui Ng², Pengcheng Zhu¹, Shunsuke Chiba⁵, Xiaomeng Wang^{2

6

7

8}, Walter Wahli^{2

9

10}, Nguan Soon Tan^{1

2

6

11}

Affiliations

¹ 1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore.
² 2Lee Kong Chian School of Medicine, Nanyang Technological University, Novena Campus, 11 Mandalay Road, Singapore, 308232 Singapore.
³ 3Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, 17177 Stockholm, Sweden.
⁴ 4Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785006 India.
⁵ 5School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371 Singapore.
⁶ 6Institute of Molecular and Cell Biology, Agency for Science Technology & Research, 61 Biopolis Drive, Proteos, Singapore, 138673 Singapore.
⁷ 7Department of Cell Biology, Institute of Ophthalmology, University College London, London, UK.
⁸ 8Singapore Eye Research Institute, Singapore, 169856 Singapore.
⁹ INRA ToxAlim, Chemin de Tournefeuille, Toulouse Cedex 3, UMR1331 France.
¹⁰ 10Center for Integrative Genomics, University of Lausanne, Le Genopode, Lausanne, Switzerland.
¹¹ KK Research Centre, KK Women's and Children Hospital, 100 Bukit Timah Road, Singapore, 229899 Singapore.

Abstract

Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre-Pparb/d^-/-) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d^-/- mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis.