Daily Endocrinology Research Analysis
Three impactful studies advance endocrine-metabolic science: (1) a human GR variant (rs6190) mechanistically elevates cholesterol and atherosclerosis via hepatic PCSK9/BHLHE40 with sex-specific effects; (2) periportal THRSP–MIF–CD74+ lipid-associated macrophage crosstalk drives MASH and is druggable with a small-molecule inhibitor; (3) a multimodal, explainable AI integrating fundus imaging and clinical data predicts 5‑year CKD risk in type 2 diabetes across binational cohorts.
Summary
Three impactful studies advance endocrine-metabolic science: (1) a human GR variant (rs6190) mechanistically elevates cholesterol and atherosclerosis via hepatic PCSK9/BHLHE40 with sex-specific effects; (2) periportal THRSP–MIF–CD74+ lipid-associated macrophage crosstalk drives MASH and is druggable with a small-molecule inhibitor; (3) a multimodal, explainable AI integrating fundus imaging and clinical data predicts 5‑year CKD risk in type 2 diabetes across binational cohorts.
Research Themes
- Sex-specific genetic mechanisms driving dyslipidemia and atherosclerosis
- Immunometabolic crosstalk and spatial zonation in fatty liver disease (MASLD/MASH)
- Explainable multimodal AI for chronic kidney disease risk prediction in type 2 diabetes
Selected Articles
1. The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis.
A common GR coding variant (rs6190) elevates circulating cholesterol and atherosclerosis risk via hepatic transactivation of PCSK9 and BHLHE40, suppressing LDLR/HDLR. The effect shows sex specificity: attenuated by corticosterone/testosterone in males and additive with estrogen loss in females; mechanisms validate in CRISPR-edited human hepatocyte-like cells.
Impact: It uncovers a GR-dependent, targetable pathway linking a prevalent human variant to dyslipidemia and atherosclerosis with clear sex-specific biology, integrating human population data with mechanistic in vivo and in vitro validation.
Clinical Implications: Highlights PCSK9/BHLHE40 as mediators of GR-driven hypercholesterolemia, supporting intensified lipid-lowering (e.g., PCSK9 inhibition) in genetically at‑risk women and prompting consideration of sex hormones’ modulatory roles.
Key Findings
- rs6190 associates with higher cholesterol in women in UK Biobank and All of Us.
- SNP-genocopy mice show hepatic GR-driven transactivation of Pcsk9 and Bhlhe40, elevating all lipoprotein fractions and atherosclerosis.
- Liver knockdown of Pcsk9/Bhlhe40 abrogates atherogenesis; CRISPR-edited human hepatocyte-like cells recapitulate the mutant program.
- Corticosterone/testosterone mitigate, while estrogen loss augments, the mutant GR lipid program.
Methodological Strengths
- Convergent evidence from large human cohorts (UK Biobank, All of Us), SNP-genocopy mice, and CRISPR-edited human iPSC-derived hepatocytes.
- Causal pathway interrogation via in vivo liver knockdown of Pcsk9 and Bhlhe40 with sex-hormone modulation experiments.
Limitations
- Translational extrapolation from mouse hAPOE*2/*2 background to human pathophysiology may not fully capture complexity.
- Population associations, while robust, are observational and do not quantify clinical benefit of targeted interventions.
Future Directions: Assess clinical lipid/atherosclerosis outcomes by rs6190 genotype under PCSK9 inhibition and evaluate sex hormone interactions; explore BHLHE40 as a therapeutic target.
2. MIF-mediated crosstalk between THRSP + hepatocytes and CD74 + lipid-associated macrophages in hepatic periportal zone drives MASH.
Spatial transcriptomics pinpoints periportal THRSP-high hepatocytes as hubs recruiting CD74+ LAMs through MIF, driving MASH. THRSP augments palmitate via de novo lipogenesis and prevents FASN ubiquitination (FASN–TRIM21 disruption). A small-molecule THRSP inhibitor (C6) significantly ameliorates MASH in mice.
Impact: It elucidates spatially resolved immunometabolic crosstalk underpinning MASH and validates THRSP as a druggable node with a proof‑of‑concept small-molecule inhibitor that reverses disease in vivo.
Clinical Implications: Supports targeting THRSP–MIF–CD74+ LAM axis for MASH therapy, prioritizing periportal processes and offering a new class of agents beyond metabolic/anti-inflammatory standards.
Key Findings
- Periportal zones in MASH show increased myeloid cells and THRSP-high hepatocytes.
- THRSP drives MASH by MIF-mediated recruitment of CD74+ lipid-associated macrophages.
- THRSP increases palmitate via de novo lipogenesis and blocks FASN ubiquitination by disrupting FASN–TRIM21.
- A THRSP inhibitor (C6) significantly ameliorates MASH in mice.
Methodological Strengths
- Spatial transcriptomics with ligand–receptor inference (CellPhoneDB) and in situ co-localization.
- Mechanistic gain/loss-of-function with pathway dissection and in vivo therapeutic testing of a novel inhibitor.
Limitations
- Preclinical models; human causal validation and safety/PK of C6 are pending.
- Quantitative contribution of periportal vs pericentral zones in human MASH progression remains to be defined.
Future Directions: Advance THRSP inhibitors to IND-enabling studies; biomarker development for periportal THRSP/MIF/CD74 activity; patient stratification by zonation signatures.
3. A Multimodal Predictive Model for Chronic Kidney Disease and Its Association With Vascular Complications in Patients With Type 2 Diabetes: Model Development and Validation Study in South Korea and the U.K.
An ensemble multimodal model combining fundus photographs (VGG16) and clinical data (DNN) achieved AUC 0.88 internally and 0.72 externally for 5‑year incident CKD in T2D. Explainability (SHAP/Grad‑CAM) highlighted eGFR and optic disc features; higher model probabilities aligned with elevated macro- and microvascular event risks.
Impact: Demonstrates clinically actionable, explainable AI integrating imaging and clinical modalities for CKD risk stratification across diverse cohorts, linking predictions to vascular outcomes.
Clinical Implications: Supports fundus-and-clinical multimodal screening to identify high-risk T2D patients for CKD prevention, earlier nephroprotective therapy, and vascular risk management.
Key Findings
- Internal AUC 0.880 and external AUC 0.722 for 5-year incident CKD prediction in T2D using fundus images plus clinical data.
- Explainability identified eGFR and optic disc features as key predictors (SHAP, Grad‑CAM).
- Higher model probability associated with increased macrovascular (HR up to 1.64) and microvascular (HR 1.30) risks.
Methodological Strengths
- Large discovery cohort with external validation in UK Biobank, enhancing generalizability.
- Explainable AI (SHAP/Grad-CAM) clarifies imaging and clinical feature contributions.
Limitations
- External performance attenuation (AUC 0.722) indicates domain shift; prospective impact studies are needed.
- CKD definition includes codes and eGFR thresholds; potential misclassification bias.
Future Directions: Prospective deployment with clinical decision support to test outcome improvement; domain adaptation to enhance cross-population performance; integration with nephroprotective treatment pathways.