The Follistatin‐like Protein 1 Pathway Is Important for Maintaining Healthy Articular Cartilage

Chaly, Yury; Hostager, Bruce S.; Smith, Sonja; Hirsch, Raphael

doi:10.1002/acr2.11155

Cited by 7 publications

(5 citation statements)

References 57 publications

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“…To screen the receptors of FSTL1 that is/are responsible for the liver phenotypes in F4MKO mice, we measured the expression of their transcripts. Twelve receptors were reported to be related to FSTL1 33 – 36 . According to sc-RNA-Seq data from human and mouse livers, these 12 receptors were expressed in different patterns in different cell types (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis

Guo,

Feng,

Zhu

et al. 2023

Nat Commun

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Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

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Section: Resultsmentioning

confidence: 99%

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis

Guo,

Feng,

Zhu

et al. 2023

Nat Commun

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“…Thus, in addition to blocking effects of BMP4, there appears to be at least one other pathway by which FSTL1 affects permeability. Note that noggin does not inhibit BMP9, and that FSTL1 binds to Alk1 [ 28 ]; both BMP9 and ALK1 are involved in the regulation of transcytosis [ 22 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial cells exposed to atheroprotective flow secrete follistatin-like 1 protein which reduces transcytosis and inflammation

et al. 2021

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Background and aims: When endothelium is cultured in wells swirled on an orbital shaker, cells at the well centre experience putatively atherogenic flow whereas those near the edge experience putatively atheroprotective flow. Transcellular transport is decreased equally in both regions, consistent with it being reduced by a mediator released from cells in one part of the well and mixed in the swirling medium. Similar effects have been inferred for pro-inflammatory changes. Here we identify the mediator and flow characteristics stimulating its release. Methods and results: Medium conditioned by cells swirled at the edge, but not by cells swirled at the centre or cultured under static conditions, significantly reduced transendothelial transport of a low density lipoprotein (LDL)-sized tracer and tumor necrosis factor α (TNF-α)-induced activation and translocation of nuclear factor κB (NF-κB), adhesion molecule expression and monocyte adhesion. Inhibiting transcytosis similarly decreased tracer transport. Unbiased proteomics revealed that cells from the swirled edge secreted substantially more follistatinlike 1 (FSTL1) than cells from the swirled centre or from static wells. Exogenous FSTL1 reduced transport of the LDL-sized tracer and of LDL itself, as well as TNF-α-induced adhesion molecule expression. Bone morphogenetic protein 4 (BMP4) increased transport of the LDL-sized tracer and adhesion molecule expression; FSTL1 abolished these effects. Conclusions: Putatively atheroprotective flow stimulates secretion of FSTL1 by cultured endothelial cells. FSTL1 reduces transcellular transport of LDL-sized particles and of LDL itself, and inhibits endothelial activation. If this also occurs in vivo, it may account for the atheroprotective nature of such flow.

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“…To screen which receptor(s) of FSTL1 is/are responsible for the liver phenotypes in F4MKO mice, we measured the transcripts of them. 12 receptors were reported to be related to FSTL1 31,32,33,34 . According to sc-RNAseq from human and mouse liver, these 12 receptors expressed different patterns in different cell types (Extended Data Fig.…”

Section: Skeletal Muscle Irf4 Regulated Liver Metabolism Via Fstl1-di...mentioning

confidence: 99%

Metabolic crosstalk between skeletal muscle and liver through IRF4-FSTL1 in NASH

Guo

Feng

Zhu

et al. 2022

Preprint

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Inter-organ crosstalk has gained more and more attention recently. However, the mechanisms under this remain incompletely understood. Here, we revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice showed ameliorated liver steatosis, inflammation, and fibrosis, without changes in body weight on nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis of serum suggested that follistatin-like protein 1 (FSTL1) might link the communication between muscle and liver. Dual luciferase assays showed that IRF4 could transcriptionally regulate FSTL1 and reconstitution of FSTL1 expression in muscle of F4MKO mice was sufficient to restore the liver pathology. Furthermore, co-culture experiments verified that different receptors contribute to FSTL1’s function in different cell types of liver. Finally, we found serum FSTL1 level was positively correlated with NASH progression in human. These data unveiled a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-DIP2A/CD14 in the pathogenesis of NASH.

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The Follistatin‐like Protein 1 Pathway Is Important for Maintaining Healthy Articular Cartilage

Cited by 7 publications

References 57 publications

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis

Endothelial cells exposed to atheroprotective flow secrete follistatin-like 1 protein which reduces transcytosis and inflammation

Metabolic crosstalk between skeletal muscle and liver through IRF4-FSTL1 in NASH

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