OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models...OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models.METHODS We examined metrnl tissue expression pattern in a human tissue microarray containing 19types of tissues from 69 donors,and verified the highest expression in fresh human and mouse tissues.We then created an animal model of cell-specific knockout mice to study the role of metrnl.RESULTS Metrnl was the highest expressed in human gastrointestinal tract,and specifical y expressed in the intestinal epithelium.Consistently,Metrnl expression was also the highest expressed in mouse gastrointestinal tract among the detected tissues of 14 types.We developed intestinal epithelial cellspecific metrnl knockout mice with Vil in-Cre.In this animal model,metrnl levels displayed a statistically significant reduction in gut fluid,but not in blood serum.This cell specific deletion of metrnl did not affect body weight,food intake,blood glucose,colon length and histology,intestinal permeability,mucus production and mucin 2 expression under physiological conditions,but markedly reduced the expression of antimicrobial peptides,such as regenerating islet-derived 3 gamma and lactotransferrin.CONCLUSION Metrnl is rich in intestinal epithelial cells of humans and mice,mainly contributing to local gut metrnl level,and less affecting systemic circulating metrnl level.Metrnl plays a role in maintaining gut antimicrobial peptides.展开更多
METRNL is a recently identified secreted protein with emerging functions.This study is to find major cellular source of circulating METRNL and to determine METRNL novel function.Here,we show METRNL is abundant in huma...METRNL is a recently identified secreted protein with emerging functions.This study is to find major cellular source of circulating METRNL and to determine METRNL novel function.Here,we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway.By creating endothelial cell-specific Metrnl knockout mice,combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl,we demonstrate that most of circulating METRNL(approximately 75%)originates from the endothelial cells.Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients.By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice,combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice,we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis.Mechanically,endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway,which promotes the susceptibility of atherosclerosis.Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction.These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease.METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.展开更多
基金The project supported by National Natural Science Foundation of China(81130061,81202572,81373414)
文摘OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models.METHODS We examined metrnl tissue expression pattern in a human tissue microarray containing 19types of tissues from 69 donors,and verified the highest expression in fresh human and mouse tissues.We then created an animal model of cell-specific knockout mice to study the role of metrnl.RESULTS Metrnl was the highest expressed in human gastrointestinal tract,and specifical y expressed in the intestinal epithelium.Consistently,Metrnl expression was also the highest expressed in mouse gastrointestinal tract among the detected tissues of 14 types.We developed intestinal epithelial cellspecific metrnl knockout mice with Vil in-Cre.In this animal model,metrnl levels displayed a statistically significant reduction in gut fluid,but not in blood serum.This cell specific deletion of metrnl did not affect body weight,food intake,blood glucose,colon length and histology,intestinal permeability,mucus production and mucin 2 expression under physiological conditions,but markedly reduced the expression of antimicrobial peptides,such as regenerating islet-derived 3 gamma and lactotransferrin.CONCLUSION Metrnl is rich in intestinal epithelial cells of humans and mice,mainly contributing to local gut metrnl level,and less affecting systemic circulating metrnl level.Metrnl plays a role in maintaining gut antimicrobial peptides.
基金supported by grants from the National Natural Science Foundation of China Major Project(Nos.81730098 and 82030110)National Natural Science Foundation of China Young Program(No.82104165)+2 种基金Shanghai Science and Technology Commission Project(No.201409004600,China)Shanghai Sailing Program(No.21YF1457600,China)Medical Innovation Project(Nos.16CXZ009,16QNP087 and 2018-CGPZ-A03,China)。
文摘METRNL is a recently identified secreted protein with emerging functions.This study is to find major cellular source of circulating METRNL and to determine METRNL novel function.Here,we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway.By creating endothelial cell-specific Metrnl knockout mice,combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl,we demonstrate that most of circulating METRNL(approximately 75%)originates from the endothelial cells.Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients.By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice,combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice,we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis.Mechanically,endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway,which promotes the susceptibility of atherosclerosis.Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction.These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease.METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.
