TM7SF3 Controls TEAD1 Splicing to Prevent MASH-Induced Liver Fibrosis

Endocrinology Hepatobiliary System Biochemistry Basic Medical Sciences Life Sciences Immunology Gastroenterology Medicine Cell Biology
TM7SF3 TEAD1 Liver fibrosis MASH HSC activation

Background Introduction

In modern society, metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD) is a common and serious chronic liver disease. However, the current understanding of its pathological mechanisms is not complete, including its progression to metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and its substantial pathophysiological processes. Liver fibrosis is a major predictor of mortality and adverse liver events in MASH patients, primarily due to the activation of hepatic stellate cells (HSC). Inhibiting the activation of HSC is crucial to stopping and reducing fibrosis in MASH.

The Hippo signaling pathway and TEAD1 (transcriptional enhanced associate DNA-binding domain transcription factor 1) are factors found to be closely related to various diseases such as inflammation, fibrosis, and cancer in existing studies. However, how TEAD1 plays a role in hepatic stellate cells has not been thoroughly researched. This study focuses on exploring the regulatory mechanism of an intranuclear seven-transmembrane protein TM7SF3 on TEAD1 splicing, to investigate its key role in preventing liver fibrosis induced by MASH.

Source of the Paper

This study was completed by Roi Isaac, Gautam Bandyopadhyay, Theresa V. Rohm, and others from the Department of Endocrinology and Metabolism at the University of California, San Diego (UCSD), under the guidance of Professor Jerrold M. Olefsky. The study was published in the journal “Cell Metabolism” on May 7, 2024, and the article’s DOI is https://doi.org/10.1016/j.cmet.2024.04.003.

Research Details

Research Process

The research explored the impact of TM7SF3 on HSC activation and liver fibrosis through a series of experimental steps. The main process is as follows:

1. Knockout Experiment of Nuclear Protein TM7SF3 Firstly, the research team studied the role of TM7SF3 in the activation process of HSCs using TM7SF3 knockout mice (KO mice) and human HSC models. The effect of TM7SF3 knockout on the expression of fibrosis-related genes in HSCs was measured by quantitative PCR (qPCR).

2. Exploration of TEAD1 Splicing Mechanism Further experiments using qPCR detected that TM7SF3 knockout leads to the selective splicing of the Hippo signaling pathway transcription factor TEAD1, thereby producing a more active form of TEAD1 lacking the fifth exon (TEAD1ΔEx5).

3. Antisense Oligonucleotide (ASO) Intervention Experiment The study also used a specific antisense oligonucleotide (ASO) to interfere with the alternative splicing of TEAD1. The results showed that inhibition of HSC activation by ASO effectively reduced the degree of liver fibrosis induced by the MASH diet.

4. HSC-TM7SF3KO Model Experiment In addition, the study used an HSC-specific TM7SF3 knockout model by breeding TM7SF3 floxed mice with Lrat-Cre mice. This further verified the effect of TM7SF3 specific knockout on MASH-induced liver fibrosis, observing a significant increase in fibrosis and inflammatory markers through liver tissue detection.

Main Research Results

1. TM7SF3 Knockout Leads to HSC Activation: In TM7SF3 knockout mice and human HSCs, a significant increase was observed in the expression of fibrosis-related genes such as TGFβ1, Col1A1, TIMP1, and MCP1, indicating that TM7SF3 plays a key role in inhibiting HSC activation and fibrosis.

2. Alternative Splicing Mechanism of TEAD1: TM7SF3 interacts with the RNA-binding protein hnRNP (heterogeneous nuclear ribonucleoprotein U) to inhibit it from splicing pre-mRNA of TEAD1 into the more active TEAD1ΔEx5 form.

3. Efficacy of Antisplicing Intervention: Using specific ASO to inhibit TEAD1 splicing can effectively reduce HSC activation levels and significantly decrease liver fibrosis under MASH conditions in in-vitro and in-vivo models. This demonstrates the potential application value of ASO in the treatment of MASH-related fibrosis.

4. Increase in Fibrosis and Inflammation Markers: In HSC-TM7SF3KO mice and MASH models, a significant elevation in fibrosis and inflammation markers was observed, along with an increase in serum transaminase levels, further verifying the important role of TM7SF3 in inhibiting MASH-related liver fibrosis.

Scientific and Application Value of the Research

Scientific Value

This research first revealed the critical role of TM7SF3 as a nuclear protein in regulating the alternative splicing of TEAD1, thereby inhibiting HSC activation and preventing MASH-induced liver fibrosis. It expands the understanding of the role and regulation mechanism of the Hippo signaling pathway in hepatic stellate cells.

Application Value

Intervention using specific ASO to inhibit TM7SF3 showed strong anti-HSC activation and antifibrosis effects by impeding TEAD1 splicing. It provides a new potential target for the treatment of MASH-related fibrosis, and the long-acting version of ASO56 may have great application prospects in the treatment of chronic diseases.

Research Highlights

1. New Mechanism Discovery: The study first discovered the critical role of TM7SF3 in preventing liver fibrosis by inhibiting the splicing of TEAD1 through hnRNP U.

2. ASO Analysis: The outstanding performance of specific splicing interference drugs (ASO) in in-vivo and in-vitro experiments shows its great potential in the treatment of MASH-related liver fibrosis.

3. Validation by Animal Models: Through various genetic models and diet-induced animal experiments, the specific role of TM7SF3 in the development of liver fibrosis was further verified.

Conclusion

This study proposed a new TM7SF3-HNRNPU-TEAD1 signaling mechanism, elucidating its role in regulating TEAD1 splicing in HSC activation and MASH-related fibrosis development. Particularly, the intervention using specific ASO demonstrated its potential application in inhibiting HSC activation and fibrosis therapy, providing new solutions for the treatment of chronic liver diseases.

Although the study performed well in different models, more clinical trials are needed in the future to verify the actual effects of these mechanisms in human treatment. This finding may pave the way for future treatments of liver fibrosis, especially MASH.