Evaluation of Gremlin-1 as a Therapeutic Target in Metabolic Dysfunction-Associated Steatohepatitis: Lack of Efficacy Despite Increased Hepatic Expression

Khái niệm cốt lõi

Hepatic Gremlin-1 expression is increased in metabolic dysfunction-associated steatohepatitis (MASH), but therapeutic targeting of Gremlin-1 does not reduce liver inflammation or fibrosis in in vivo and ex vivo models.

Tóm tắt

The content examines the role of Gremlin-1 as a potential therapeutic target in metabolic dysfunction-associated steatohepatitis (MASH). Key highlights:

1. Gremlin-1 expression is increased in human and rat MASH liver, localized to a small subpopulation of COL3A1/THY1+ myofibroblasts.

2. Lentiviral overexpression of Gremlin-1 in hepatic stellate cells and LX-2 cells led to changes in BMP-related gene expression, but did not translate to increased fibrogenesis.

3. Gremlin-1 binds to heparin with high affinity, preventing it from entering systemic circulation and limiting its potential for organ crosstalk.

4. Treatment with neutralizing anti-Gremlin-1 antibodies did not reduce liver inflammation or fibrosis in a rat MASH model or in human cirrhotic precision-cut liver slices.

5. The authors conclude that Gremlin-1 plays a redundant role in the pathogenesis of liver fibrosis and is not an effective therapeutic target for MASH.

Thống kê

Gremlin-1 mRNA expression was 4.8 to 9.8-fold increased in human MASH, ALD, PBC and PSC liver tissues compared to donor livers.
Gremlin-1 protein could not be detected in the circulation of healthy subjects and MASH patients.
The anti-Gremlin-1 antibody 0030:HD had an IC50 of 2.7-3.1 nM for inhibiting Gremlin-1 binding to BMP4 and an EC50 of 1.27-1.36 nM in a BMP-responsive reporter assay.
Lentiviral overexpression of GREM1 increased its expression by 177-fold in LX-2 cells and 6.3-fold in primary human hepatic stellate cells.

Trích dẫn

"Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target."
"Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting."

Thông tin chi tiết chính được chắt lọc từ

Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis

by Horn,P., Nor... lúc www.biorxiv.org 01-05-2024

https://www.biorxiv.org/content/10.1101/2024.01.03.574043v2

Yêu cầu sâu hơn

What other signaling pathways or cellular mechanisms might Gremlin-1 be involved in that could contribute to MASH pathogenesis, beyond its effects on BMP signaling?

Gremlin-1, besides its known role in inhibiting BMP signaling, may also impact other signaling pathways and cellular mechanisms that contribute to MASH pathogenesis. One potential pathway is the TGFβ signaling pathway, as Gremlin-1 has been reported to directly antagonize TGFβ1 in certain contexts. TGFβ1 is a key player in fibrogenesis and inflammation in the liver, and Gremlin-1's interaction with this pathway could modulate fibrotic responses. Additionally, Gremlin-1 has been linked to adipose tissue dysfunction, and its effects on adipogenesis and adipocyte function could indirectly influence liver pathology in MASH. Furthermore, Gremlin-1's role in driving hepatocellular senescence, as previously suggested, could contribute to the progression of liver fibrosis in MASH.

Given the lack of efficacy of targeting hepatic Gremlin-1, are there other potential therapeutic approaches targeting Gremlin-1 in extrahepatic tissues, such as visceral adipose tissue, that could be explored for MASH?

Considering the limited efficacy of targeting hepatic Gremlin-1 in MASH, exploring therapeutic approaches that target Gremlin-1 in extrahepatic tissues, particularly visceral adipose tissue, could be a promising avenue. As Gremlin-1 has been implicated in adipose tissue dysfunction and adipogenesis, interventions that modulate Gremlin-1 expression or activity in adipose tissue could potentially impact the development and progression of MASH. Strategies such as anti-Gremlin-1 antibodies or small molecule inhibitors targeting Gremlin-1 in adipose tissue could be explored to mitigate the systemic effects of Gremlin-1 on liver pathology in MASH.

How might the high-affinity heparin binding properties of Gremlin-1 be leveraged for diagnostic or prognostic applications in MASH, if it is not a suitable therapeutic target?

Although Gremlin-1's high-affinity heparin binding properties prevent its release into systemic circulation and limit its potential as a therapeutic target, these properties could be leveraged for diagnostic or prognostic applications in MASH. The avid binding of Gremlin-1 to heparin suggests that it is localized to specific tissues or extracellular matrix components, which could serve as a biomarker for tissue-specific fibrotic changes. Detection of Gremlin-1 in specific tissues or extracellular matrix regions through imaging techniques or localized sampling could provide insights into the progression of fibrosis in MASH. Additionally, the absence of detectable circulating Gremlin-1 despite its local expression highlights the importance of considering tissue-specific effects and interactions in the pathogenesis of MASH, which could inform diagnostic and prognostic strategies.