Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis.
Nancy WareingTingting W MillsScott CollumMinghua WuLucy RevercombRene GirardMarka LyonsBrian SkaugWeizhen BiMeer A AliHaniyeh KoochakAnthony R FloresYuntao YangW Jim ZhengWilliam SwindellShervin AssassiHarry Karmouty-QuintanaPublished in: bioRxiv : the preprint server for biology (2024)
Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited treatment strategies. This is in part due to our fragmented understanding of how dermal white adipose tissue (DWAT) contributes to skin fibrosis. We identified elevated sine oculis homeobox homolog 1 (SIX1) expression in SSc skin samples from the GENISOS and PRESS cohorts, the expression of which correlated with adipose-associated genes and molecular pathways. SIX1 localization studies identified increased signals in the DWAT area in SSc and in experimental models of skin fibrosis. Global and adipocyte specific Six1 deletion abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage induced by SQ bleomycin treatment. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. However, SIX1 deletion did not appear to affect cellular trans differentiation. Taken together these results point at SIX1 as a potential target for dermal fibrosis in SSc.
Keyphrases
- adipose tissue
- systemic sclerosis
- wound healing
- insulin resistance
- poor prognosis
- gene expression
- interstitial lung disease
- soft tissue
- high fat diet
- binding protein
- fatty acid
- dna methylation
- idiopathic pulmonary fibrosis
- metabolic syndrome
- genome wide
- small molecule
- climate change
- single cell
- single molecule
- amino acid
- protein protein
- smoking cessation
- genome wide identification