Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 201

Unraveling genetic mysteries: phenotype-shaping profiles in chronic sarcoidosis

ABSTRACT Background Sarcoidosis represents a complex inflammatory condition of unknown origin, characterized by diverse clinical profiles, particularly identifiable as Löfgren’s syndrome (LS) and non-LS cases. Delving into the genetic underpinnings of chronic sarcoidosis phenotypes is essential for advancing our understanding and treatment of this disease. Methods To classify chronicity, pulmonologists evaluated sarcoidosis phenotypes over a follow-up period of two years, distinguishing between chronic and nonchronic classifications. We assessed the genetics of these chronicity phenotypes in a Swedish cohort of 1,515 sarcoidosis cases (679 nonchronic and 836 chronic) alongside 3,085 controls using the Immunochip array. To confirm our findings, replication analysis was conducted in a German cohort of 1,216 sarcoidosis cases (485 nonchronic and 731 chronic) and 3,042 controls. A comprehensive meta-analysis of significant SNPs (p < 5e-8) was carried out using inverse variance weighting. Additionally, we employed gene-based analysis, enrichment mapping, and pathway analysis to gain deeper functional insights. Results Our meta-analysis uncovered significant genetic associations with chronic sarcoidosis phenotypes, including LS nonchronic (rs3135356; OR = 3.13, 95% CI: 2.38 - 4.12), non-LS nonchronic (rs2395162; OR = 2.34, 95% CI: 1.96 - 2.85), and non-LS chronic cases (rs1049550; OR = 0.68, 95% CI: 0.59 - 0.76). Specifically, gene-based analysis revealed that CLIC1 is associated with nonchronic forms, while ANXA11 is linked to the chronic phenotype. Our enrichment analysis highlighted the expression of quantitative trait loci (eQTLs) in immune cells, whole blood, and lung tissues. The pathway analysis pinpointed the antigen presentation pathway as vital to understanding chronicity phenotypes. Conclusions This study illuminates the distinct genomic features that differentiate chronic sarcoidosis phenotypes, underscoring the critical involvement of immune-related genes and regulatory networks. By advancing the knowledge of sarcoidosis chronicity, these findings pave the way for targeted therapeutic interventions and personalized treatment strategies that can significantly improve patient outcomes