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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.
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Objective To elucidate the function of phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway underlying the regulation of Na+-I-symporter (NIS) and the influence of different levels of iodine on PI3K-AKT signaling pathway in lactating breast cells.Methods The primary cultured mammary gland cells were divided into three groups:①control group [0 μmol/L LY294002 + 0 μg/L insulin-like growth factor Ⅰ (IGF-Ⅰ)];②stimulation group (50 μg/L IGF-Ⅰ);③inhibition group (40 μmo]/L LY294002 + 50 μg/L IGF-Ⅰ).In addition,the cells were treated with different iodine contents (0,5,50,1 000,3 000 μg/L) for low iodine groups 1 and 2,iodine group,high iodine groups 1 and 2,and IGF-Ⅰ (50 μg/L) was used to stimulate PI3K-AKT signaling pathway.The expressions of AKT and NIS mRNA and protein were determined by real-time quantitative PCR and Western blotting,respectively.Results The expression of AKT mRNA (1.497 ± 0.550) in stimulation group was higher than that in inhibition group (0.777 ± 0.108,P ＜ 0.05),while the expression of NIS mRNA and protein in stimulation group (0.783 ± 0.187,0.618 ± 0.103) was lower than those in inhibition group (2.430 ± 1.423,1.417 ± 0.250,all P ＜ 0.05).With the iodine concentration increasing,except high iodine group 1 (1.090 ± 0.356),the expression of AKT mRNA in low iodine groups 1 and 2,iodine group,high iodine group 2 (1.758 ± 0.893,1.320 ± 0.538,1.003 ± 0.006,0.745 ± 0.307) tended to decline;total AKT protein (0.640 ± 0.106,0.601 ± 0.081,0.583 ± 0.089,0.555 ± 0.097,0.532 ± 0.023) and NIS mRNA (2.259 ± 0.682,1.823 ± 0.332,1.409 ± 0.366,1.321 ± 0.405,1.150 ± 0.454) tended to decline in low iodine groups 1 and 2,iodine group,high iodine groups 1 and 2;except low iodine group 2 (0.484 ± 0.179),NIS protein expression tended to decline (0.556 ± 0.199,0.502 ± 0.179,0.455 ± 0.126,0.435 ± 0.138);however,except low iodine group 2 (0.076 ± 0.045),the p-AKT protein expressions (0.078 ± 0.049,0.079 ± 0.040,0.085 ± 0.055,0.095 ± 0.051) were on the rise.Conclusion PI3K-AKT signaling pathway may play an inhibition role in the expression of NIS in lactating breast cells.
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Objective To explore the relationship between iodine-rich diet and thyroid cancer.Methods PubMed,Excerpt Medica Database (EMbase),China National Knowledge Infrastructure (CNKI),WanFang,WeiPu,and China Biology Medicine disc (CBM) were searched through computer,for relevant articles published before June 2016,to find case-control studies concerning the relationship between iodine-rich diet and thyroid cancer.According to the inclusion and exclusion criteria for data extraction and quality evaluation,Meta-analysis was performed using Stata 12.0.Results Totally 19 case-control studies were included in this study.Cases and controls were 47 316 people (case 6 662,control 40 654).The quality of the literature was reliable (the score was 6 points and more).Meta analysis results showed a total of 13 articles studied fish,more frequent intake (3 times per week and more) of fish can reduce the risk of thyroid cancer [odds ratio (OR) =0.87,95％ confidence interval (CI):0.77-0.98,P ＜ 0.05];except saltwater fish,a total of 16 articles studied seafood,more frequent intake of seafood (3 times per week and more) increases the risk of thyroid cancer (OR =1.48,95％CI:1.11-1.99,P＜ 0.05).Study factors subgroup analysis showed that seafood (OR =2.23,95％CI:1.45-3.45,P ＜ 0.05),marine animal food (OR =9.48,95％CI:5.03-17.88,P ＜ 0.05) and seaweed (OR =1.93,95％CI:1.39-2.69,P ＜ 0.05) can increase the risk of thyroid cancer,shellfish (OR =1.21,95％CI:0.94-1.56,P ＞ 0.05),saltwater fish (OR =0.94,95％CI:0.50-1.77,P ＞ 0.05)and freshwater fish (OR =0.90,95％CI:0.66-1.21,P ＞ 0.05) had no effect on the prevalence of thyroid cancer.Conclusion Seafood,marine animal foods and seaweed will increase the risk of thyroid cancer.
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Objective To systematically review the prevalence of hypothyroidism from 2000 to 2016 in China.Methods Twenty-five researches were selected from the database of Wanfang,CNKI,CBM,PubMed and Embass according to the inclusion and exclusion criteria and reviewed systematically.Overall prevalence and 95％CI were calculated and forest plots were drawn by Stata 12.0.Results Based on the results from the existing data,the prevalence of hypothyroidism was 9.3％ (7.1％ for male and 12.2％ for female),compared with the group of 60 and over (11.8％),other age groups had lower prevalence of hypothyroidism (the groups of 18-＜ 40 and 40-＜ 60 was 7.4％ and 9.1％,respectively).The prevalence of clinical hypothyroidism and subclinical hypothyroidism was 1.1％ and 8.7％,respectively.In northwest area,the prevalence of hypothyroidism (14.9％) was significantly higher than those of other regions (the east area was 7.7％,north area was 8.0％,southwest area was 13.4％).The prevalence of hypothyroidism from 2011 to 2016 (10.8％) was higher than those of 2002 to 2010 (5.0％).The prevalence of iodine excess group (15.3％) was higher than that of iodine adequate group (8.9％) and that of iodine deficiency group (3.0％).Conclusion The prevalence of hypothyroidism in China has a tendency to increase in recent years,and the preventive and curative strategies to control hypothyroidism need to be further studied.