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iNature
Liver injury is the starting point for many liver diseases and is therefore often the birthplace
of breakthrough research in the field of liver.
Drug-induced liver injury (DILI) is the most common serious adverse drug reaction and the leading cause of acute liver failure, which has a very high mortality rate and limited
treatment.
In recent years, with the widespread use of traditional Chinese medicine, antibiotics and antitumor drugs, the disease burden of DILI in Chinese mainland has increased year by year, which is significantly higher than that of other countries
.
Therefore, it is of great clinical significance
to elucidate the core pathogenesis of DILI to find key drug intervention targets.
On November 8, 2022, Professor Yang Changqing's team from the Department of Gastroenterology of Tongji Hospital affiliated to Tongji University published an online article entitled " Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice The study revealed the key position and core mechanism of Mas signaling in the DILI process, providing important data support
for the development of new targets for drug intervention.
of being an ideal target for drug intervention.
Mas is widely expressed in a variety of tissues of humans and mice, and its natural ligand is angiotensin (1-7), which is an important effector molecule of the "anti-inflammatory" renin-angiotensin system, so in theory, activating Mas may have multiple beneficial effects such as improving lipid metabolism disorders, anti-inflammatory, antioxidant and so on, but there are no studies involving the role of
Mas in the DILI process.
Professor Yang Changqing's team first detected a significant upregulation
of Mas expression levels locally in the livers of DILI patients.
Multiplex fluorescent immunohistochemical staining showed low expression of Mas in hepatocytes and high levels in myeloid-derived monocyte-macrophages and neutrophils
.
The researchers then carried out a series of functional experiments to confirm that the upregulation of Mas expression in liver cells in the DILI process is a protective feedback of the body in response to liver damage, but it is not enough to completely combat drug-induced liver damage
.
Figure 1 The expression pattern of Mas in DILI patients, acetaminophen (APAP), acetaminophen (APAP), is one of
the main pathogenic drugs causing acute liver failure.
Since the mouse AILI model highly replicates the pathophysiological mechanism of human AILI, it is most widely used in the research field of DILI
.
In this study, the researchers first found that the phenotype of AILI (including the degree of liver damage and inflammation) caused by knockout of the generalized, local and hepatocyte-specific Mas1 gene was highly similar, which strongly confirmed the key role
of hepatocyte Mas signaling in the process of AILI in mice.
In addition, by intraperitoneal injection of the Mas receptor-specific agonist AVE0991, the systemic activation of Mas receptor in vivo can be effectively prevented and treated in mice
.
Lipid autophagy (referred to as lipophagy) is a special type of autophagy that selectively recognizes lipid droplets and efficiently integrates them into autophagies, using lysosomal enzymes to break down triglycerides to produce free fatty acids, providing substrates for fatty acid oxidation (FAO), which is an important metabolic pathway
for the body to reduce lipid toxicity.
The researchers found that in AILI mouse models, Mas signal loss was often accompanied by damage to the two major effect pathways of lipophagy and FAO, while activation of Mas could significantly upregulate the levels of
lipophagy and FAO.
Through the combined application analysis of transcriptome, proteome, non-targeted metabolome and targeted lipidome, the researchers screened out the AKT-FOXO1 signaling molecular pathway as the key pathway for Mas to regulate lipophagy and FAO changes in AILI, and rigorously demonstrated
it through in vitro and in vivo experiments.
Figure 2 Mas regulates APAP-induced hepatocytes injury through AKT and FOXO1 signaling molecules In order to more intuitively demonstrate Mas' regulatory effect on inflammatory cells, the researchers also used the digital adaptive optics scanning lightfield mutual iterative developed by the Institute of Brain and Cognitive Sciences of Tsinghua University tomography, DAOSLIMIT), vividly presents the movement trajectories
of neutrophils and monocytes in the liver of mice in the process of acute AILI with ultra-high spatiotemporal resolution.
DAOSLIMIT technology greatly improves the observation time and spatiotemporal resolution of in vivo 3D imaging, significantly reduces phototoxicity, and realizes millisecond-level high-speed continuous observation of mammals for several hours in vivo for the first time in the world, providing a new path for revealing the multicellular interaction between mammalian living cells, and was published in the famous academic journal Cell in 2021
.
The data presented in this study is also the first application
of DAOSLIMIT in liver disease research.
Fig.
3 Effect of Mas signal on neutromic and mononuclear macrophages under DAOSLIMIT field of viewThe above findings were highly praised by reviewers at the review stage as a major breakthrough in the AILI process, which can write a new vision for the treatment of AILI in the future The result has been magnificent and the results of transcendence in the field of acetaminophen poisoning.
They add knowledge and propose a new path in its treatment）
。 Figure 4 Overview of research methods and mechanism Chen Shuai, doctoral student of Tongji University School of Medicine, Lu Zhi, doctoral student of Department of Automation of Tsinghua University, doctoral students Jia Haoyu and Yang Bo of Tongji University School of Medicine are co-first authors of the paper, and Professor Yang Changqing and Associate Professor Li Jing of the Department of Gastroenterology of Tongji University Affiliated to Tongji University are co-corresponding authors
.
Chen Shuai, Jia Haoyu and Yang Bo are all PhD candidates of Professor Yang Changqing
.
Tongji Hospital affiliated to Tongji University is the first and corresponding author
of the paper.
The Institute of Brain and Cognitive Science of Tsinghua University has provided important technical support
for the research.
The research won the key project of the National Natural Science Foundation of China (No.
818201008006) and the key discipline construction project of "Spreading Two Wings" of Shanghai Municipal Health Commission (No.
818201008006).
SHSLCZDZK06801) and the original exploration project of the Natural Science Foundation of Shanghai Municipal Science and Technology Commission (No.
21ZR1481600).
As a clue, Professor Yang Changqing's team applied for and was approved as a key project of the National Natural Science Foundation of China (regional association) this year, which provides the possibility
for further exploration of the role of Mas in a variety of liver diseases.
Reference: style="margin-right: auto;margin-left: auto;outline: 0px;width: 30px;display: inline-block;">
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The content is [iNature]
