Daily Endocrinology Research Analysis

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a frequent consequence of Western diet consumption and liver steatosis. IL-18 binding protein (IL-18BP) limits the action of interleukin-18 (IL-18). Our work aims to study the unknown role of IL-18BP in MASH progression. METHODS: We analyzed the liver transcriptome from MASH patients. We investigated cell-specific expressions of IL-18, IL-18BP, and IL-18 receptor in human and mouse liver. We studied the liver phenotype of Il18bp-/- mice on a high-fat/high-cholesterol (HFHC) diet. We administered an anti-IL-18 antibody in Il18bp-/- mice and in diet-induced wild-type (WT) MASH mice. We generated and studied double knock-out Il18bp-/-Ifng-/- mice. RESULTS: IL-18BP expression is increased in the liver of patients and mouse models with MASH and positively correlates with fibrosis stages. On the HFHC diet, Il18bp-/- mice exhibit increased hepatic damage, inflammation, and fibrosis compared with WT mice. Treatment with anti-IL-18 antibody corrects liver defects in Il18bp-/- mice and ameliorates inflammation and fibrosis in diet-induced MASH mice, suggesting a translational treatment opportunity. Genetic deficiency in IFN-γ abrogates inflammation but not fibrosis in Il18bp-/- mice. CONCLUSIONS: IL-18BP has a role in limiting the progression of MASH, notably by reducing inflammation and fibrosis. Downstream IL-18 over-signaling, IFN-γ, mediates inflammation, but not fibrosis. Increasing IL-18BP levels represents a novel therapeutic perspective for patients affected by MASH.

OBJECTIVE: To investigate the effect of dapagliflozin on ameliorating type 2 diabetic kidney disease by regulating PRMT1-SIRT1-FoxO1-mediated autophagy and its underlying molecular mechanism, and to elucidate its role in delaying the progression of diabetic kidney disease. METHODS: A total of twelve C57BL/6J mice with diabetic kidney disease were randomly allocated into the diabetic kidney disease group (DK group) and the dapagliflozin-treated group (Dap group), with a healthy control group (NC group) additionally established (n = 6 per group). Mice in the Dap group received dapagliflozin via oral gavage, whereas those in the DK and NC groups were administered equivalent volumes of saline for 8 consecutive weeks. Upon completion of the intervention, biochemical parameters were measured. Renal ultrastructural alterations were examined by transmission electron microscopy. Differentially expressed proteins were screened using label-free quantitative proteomics. Furthermore, the expression levels of proteins in the PRMT1-SIRT1-FoxO1 pathway and the autophagy markers LC3 and p62 were validated by Western blot, RT-PCR, and immunofluorescence staining. RESULTS: Under electron microscopy, the Dap group exhibited milder glomerular lesions compared to the DKD group (p < 0.05). Levels of Scr, UAlb, BUN, and TC in the Dap group were significantly lower than those in the DKD group (p < 0.05). Compared with the DK group, the Dap group showed significantly reduced protein and mRNA expression levels of PRMT1 in renal tissue (p < 0.05), while the protein and mRNA expression levels of SIRT1, FoxO1, and its downstream autophagy-related proteins LC3-II/LC3-I, Beclin-1, Atg7, and Atg12 were significantly increased (p < 0.05). CONCLUSIONS: Dapagliflozin restores podocyte autophagic activity by regulating the PRMT1-SIRT1-FoxO1 pathway, thereby ameliorating renal function and pathological injury in diabetic kidney disease.

BACKGROUND: Adipose tissue influences cardiometabolic health through its endocrine activity and its role in regulating inflammation, lipid metabolism, and cardiovascular function. The expression of cardiac-associated genes within adipose tissue may reflect or contribute to cardiometabolic risk, yet this relationship remains poorly understood. This study investigates the expression profiles of the cardiac function associated genes GJA1, DES, DSP and SMOC2 in human adipose tissue, and analyses their associations with cardiometabolic traits. Additionally, we explore epigenomic mechanisms that may underlie their differential gene expression. METHODS: Expression profiling and functional enrichment analyses were conducted to identify depot-specific cardiac gene expression patterns. Quantitative PCR validated gene expression in paired subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples from 78 individuals with obesity. Gene expression was further validated in three independent cohorts (N = 1,548 total). Associations with clinical traits were assessed using Spearman correlations and multivariate linear regression, adjusted for age, sex, and BMI. Integration with transcriptomic and proteomic datasets publicly available from the Adipose Tissue Knowledge Portal was performed to strengthen clinical relevance. Epigenomic profiling using genome-wide ChIP-seq for histone marks (H3K4me3, H3K4me1, H3K27ac, H3K27me3) was conducted in paired SAT and OVAT samples from five individuals. RESULTS: DES, DSP, GJA1, and SMOC2 were significantly upregulated in OVAT compared to SAT. DES, DSP, and SMOC2 showed consistent expression patterns across all cohorts, while GJA1 exhibited context-dependent regulation. Gene expression in SAT was negatively correlated with cardiometabolic traits, including blood pressure, insulin resistance, and liver function markers. These associations were confirmed by regression analysis and supported by publicly available multi-omics data. Epigenetic analyses revealed OVAT-specific enrichment of active histone marks and reduced repressive marks, supporting higher differential transcriptional activity in OVAT. CONCLUSIONS: Depot-specific gene expression of DES, DSP, and SMOC2 in adipose tissue is robustly linked to cardiometabolic traits and supported by distinct epigenetic landscapes in OVAT vs SAT, highlighting their potential as novel biomarkers for cardiometabolic health.