Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in MASLD. Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. scEMC10 promoted, while mEMC10 suppressed the activation of hepatocytic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated hepatic ER stress and steatosis in mice challenged with either a MCD diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented hepatosteatosis in mice with fatty liver, suggesting a progressive role of scEMC10 in MASLD. Clinically, serum scEMC10 increased, while hepatic mEMC10 decreased in participants with MASLD. Correlative analysis indicated serum scEMC10 positively, whereas hepatic mEMC10 negatively correlated with liver fat content and serum ALT, AST, and GGT. These findings demonstrate a novel, isoform specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic ER stress and steatosis in mice, and associations of MASLD with different EMC10 isoforms in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies clearly provide the foundations for translation of scEMC10 modulation for the treatment of MASLD.

Purpose. This study aims to analyze the clinical characteristic of metabolic associated fatty liver disease (MAFLD) in patients with active Cushings disease (CD) and determine associations of thyroid hormones with MAFLD. Methods. Patients with active CD were included in this cross-sectional study. All subjects were assessed for hepatic steatosis by abdominal ultrasonography and thyroid functions. Demographic and clinical characteristic parameters were collected for correlation analysis and logistic analysis. Results. 290 individuals with active CD were included in Huashan hospital from January 2014 to February 2022. We found that the prevalence of CD with MAFLD was 33.79. The MAFLD group had a lower level of FT4 and a higher level of FT3/FT4 but no difference in levels of cortisol, 24h UFC, TSH, TT4, TT3, and FT3. Correlation analysis showed positive associations of TSH, TT4, TT3, FT3, and FT3/FT4 with BMI. In age-, BMI-, sex-, cortisol-, and 24h UFC-adjusted analysis, FT4 was independently associated with MAFLD in patients with CD. This association remained similar even after adjusting for the presence of metabolic syndrome components. Conclusion. Lower FT4 levels were associated with higher risk of MAFLD in patients with CD. FT4 may be used as a helpful indicator to predict MAFLD and provide novel ideas for the treatment of MAFLD in patients with CD in the future.

Context: We have recently shown that the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is upregulated in human obesity and that overexpression of scEMC10 promotes, whereas antibody neutralization of circulating scEMC10 prevents diet-induced obesity in mice. Objective: To explore associations of serum scEMC10 with body mass index (BMI), resting metabolism rate (RMR), and age in humans. Design: A cross-sectional study. Setting and Patients: A total of 833 participants from a Chinese physical examination cohort and 191 participants from the Leipzig Obesity Biobank cohort. Main Outcome Measures: Serum scEMC10 concentrations are measured using chemiluminescent immunoassay. RMR is calculated based on measurements from indirect calorimetry with an open-circuit ventilated-hood system. Results: In the Chinese physical examination cohort, a J-shaped nonlinear correlation between BMI and serum scEMC10 was identified in participants where underweight, overweight, and obese people all presented higher serum scEMC10 levels than normal weight people. Participants younger than age 30 years old exhibited significantly higher serum scEMC10 levels than those older than 50 years of age. In addition, participants aged 30 to 40 years also had significantly higher serum scEMC10 levels than those aged 50 to 60 years. In the Leipzig Obesity Biobank cohort, we observed a significantly negative correlation between serum scEMC10 and resting energy expenditure after adjusting for BMI. Participants in the highest quartile of serum scEMC10 levels had significantly lower RMR than those in the first quartile. RMR had an independently inverse association with serum scEMC10. Conclusions: Serum scEMC10 levels are negatively associated with age and RMR in humans.

Endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is an evolutionarily conserved and multifunctional factor across species. We previously reported that Emc10 knockout (KO) leads to mouse male infertility. Emc10-null spermatozoa exhibit multiple aspects of dysfunction, including reduced sperm motility. Two subunits of a Na/K-ATPase, ATP1A4 and ATP1B3, are nearly absent in Emc10 KO spermatozoa. Here, two isoforms of EMC10 were characterized in the mouse testis and epididymis: the membrane-bound (mEMC10) and secreted (scEMC10) isoforms. We present evidence that mEMC10, rather than scEMC10, is required for cytoplasm sodium homeostasis by positively regulating ATP1B3 expression in germ cells. Intra-testis mEMC10 overexpression rescued the sperm motility defect caused by Emc10 KO, while exogenous recombinant scEMC10 protein could not improve the motility of spermatozoa from either Emc10 KO mouse or asthenospermic subjects. Clinically, there is a positive association between ATP1B3 and EMC10 protein levels in human spermatozoa, whereas no correlation was proven between seminal plasma scEMC10 levels and sperm motility. These results highlight the important role of the membrane-bound EMC10 isoform in maintaining cytoplasm sodium homeostasis and sperm motility. Based on the present results, the mEMC10-Na, K/ATPase α4β3 axis is proposed as a novel mechanism underlying the regulation of cytoplasmic sodium and sperm motility, and its components seem to have therapeutic potential for asthenospermia.

Backgroud: Atherosclerosis, a leading driver of cardiovascular disease (CVD), lacks effective early therapeutic targets. Leveraging plasma proteome-wide Mendelian randomization (MR), this study identifies novel causal proteins implicated in atherosclerosis pathogenesis. Method: Genome-wide MR was conducted using cis-pQTLs from deCODE and UKB-PPP cohorts (approximately 90,000 individuals) as instrumental variables, integrating colocalization, summary-data-based MR (SMR), and HEIDI tests to validate causal proteins. Key findings were replicated in coronary artery disease (CAD) and CVD from CARDIoGRAMplusC4D and FinnGen cohorts. Proteins passing replication MR were subjected to phenome-wide association study (PheWAS). Single cell-type expression, transcriptome analyses, histological staining, and ELISA assays were used to identify candidate proteins' expression in specific cells or tissues. Results: Among 2711 proteins, 28 exhibited robust genetic associations with atherosclerosis. Five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) passed colocalization (PP.H4>0.8) and SMR validation. Replication MR and PheWAS analyses confirmed ADK, CALB2, and COMT's causal role in CAD and CVD. CALB2 was specifically enriched in mast cells in plaques and adipose tissue, with elevated plasma levels in patients with severe carotid artery stenosis (CAS). Conclusions: We identified 28 potential therapeutic targets for atherosclerosis and verified elevated plasma CALB2 levels in severe CAS patients, offering a novel therapeutic targets for future drug development.