Cellular senescence is a state of sustained cell cycle arrest that is associated with disease progression in NAFLD, but whether senescence is a marker or potential mediator of this disease remains uncertain, and the key factors involved in regulating hepatocyte senescence in NAFL

2024/12/1623:00:33 science 1654

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Author: TMZHI

Introduction: Cell senescence refers to the gradual occurrence of cell proliferation and differentiation ability and physiological functions during the process of cells performing life activities. In the process of decay, the life course of cells goes through several stages: undifferentiation, differentiation, growth, maturity, aging and death. YAP is a downstream effector of the Hippo pathway. As a co-activator of transcription and , it plays a key role in maintaining the youthful state of human adult stem cells and may have an "anti-aging" effect.

On August 22, University of Gothenburg researchers published a study in "Nature metabolism" "BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH" . This study found that BMP4 and Gremlin 1 Regulates hepatocyte senescence during the clinical progression of non-alcoholic fatty liver disease and can serve as a key target for fatty liver disease.

Doi: 10.1038/s42255-022-00620-x.

Research Background

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases, with an increasing prevalence worldwide, but for There are still many deficiencies in the understanding of pathophysiology .

Cellular senescence is a state of sustained cell cycle arrest that is associated with disease progression in NAFLD, but whether senescence is a marker or potential mediator of this disease remains uncertain, and the key factors involved in regulating hepatocyte senescence in NAFLD are still unclear. It is largely unknown. Bone morphogenetic proteins (BMPs) play widespread roles in liver diseases; however, the potential role of BMP4 in NAFLD and aging remains unclear.

Research process

02 Aging is closely related to the progression of NAFLD

Researchers first determined whether key markers of aging were related to NAFLD. By detecting the gene expression of aging markers in liver biopsy specimens, the researchers found that all aging markers were significant in NAFLD. Increased, liver fat mass (%) increases with the severity of liver disease and is closely related to liver aging markers (Figure 1). In addition, liver aging markers are associated with inflammation and liver fibrosis and are closely related to the pathological severity of non-alcoholic steatohepatitis (NASH).

Figure 1. Elevated levels of liver aging markers are associated with liver fat deposition

Highly expressed in the livers of NAFLD/NASH patients

To determine the specific roles of BMP4 and GREM1 in NAFLD, the researchers compared healthy, lean individuals with NAFLD Individuals, hepatic BMP4 and GREM1 expression were found to be increased in NAFLD and further increased in NASH. In addition, BMP4 can resist senescence induced by doxorubicin , while GREM1 enhances the effect of doxorubicin. The anti-aging effect of BMP4 depends on the downregulation of p16 and p53 and the activation of the Hippo pathway (Figure 2).

Figure 2. BMP4 can resist doxorubicin-induced aging

Machine learning determines the best predictor of NAFLD/NASH

Based on the important role of BMP4 and GREM1, researchers used machine learning methods to determine the correlation between NAFLD/NASH and GREM1/BMP4 markers were analyzed. The results show that aging markers (p21, p16), visceral fat tissue and GREM1 can be used as universal predictors for NAFLD/NASH disease prediction (Figure 3).

Figure 3. Machine learning identifies the best predictors of NAFLD/NASH

Research implications

Based on the current understanding of NAFLD/NASH, aging plays an important role in the progression of this disease. This study further identified the important role of aging in NAFLD/NASH, and based on this discovery of key targets that can regulate the progression of this disease, and constructed the corresponding prediction model , providing new insights into the translational treatment of NAFLD/NASH. strategy.

Reference:

Baboota RK, Rawshani A, Bonnet L, et al. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab. 2022 Aug 22. doi: 10.1038/s42255-022-00620-x.

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital.