Cell Discov.: co-auth.: W.Wahli

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

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

Sng MK1,2Chan JSK1Teo Z1Phua T1,3Tan EHP1Wee JWK1Koh NJN1Tan CK2Chen JP2Pal M4Tong BMK5Tnay YL5Ng XR2Zhu P1Chiba S5Wang X2,6,7,8Wahli W2,9,10Tan NS1,2,6,11.


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.

PMID: 29619245