Daily Endocrinology Research Analysis
Three high-impact endocrinology studies advance mechanistic and translational insights. A multi-omic analysis of SDHB-mutant pheochromocytoma/paraganglioma defines metastasis and treatment-resistance profiles, while two JCI mechanistic papers reveal splicing-driven lipogenesis in MASLD/MASH and identify adipocyte G0S2 as a regulator linking intracellular and intravascular lipolysis to abolish diet-induced hypertriglyceridemia.
Summary
Three high-impact endocrinology studies advance mechanistic and translational insights. A multi-omic analysis of SDHB-mutant pheochromocytoma/paraganglioma defines metastasis and treatment-resistance profiles, while two JCI mechanistic papers reveal splicing-driven lipogenesis in MASLD/MASH and identify adipocyte G0S2 as a regulator linking intracellular and intravascular lipolysis to abolish diet-induced hypertriglyceridemia.
Research Themes
- Mechanistic drivers and therapeutic checkpoints in metabolic liver disease (MASLD/MASH)
- Adipocyte–vascular lipolysis coordination and triglyceride clearance
- Multi-omic biomarkers and resistance mechanisms in endocrine tumors (SDHB-mutant PCPG)
Selected Articles
1. Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression.
Minor intron splicing is broadly disrupted during MASH progression, causing Insig1/2 intron retention, SREBP1c activation, and a switch to IDH1-driven reductive carboxylation that fuels de novo lipogenesis and ammonia accumulation to initiate fibrosis. Ammonia clearance or IDH1 inhibition blocked fibrogenesis, and Zrsr1 overexpression rescued splicing defects and disease. These define a splicing-metabolism checkpoint as a therapeutic target in MASLD/MASH.
Impact: Reveals a previously unappreciated splicing-driven metabolic switch that mechanistically links lipogenesis to fibrosis in MASH with actionable nodes (IDH1, ammonia, splicing factors). This could reshape therapeutic development in MASLD.
Clinical Implications: Suggests testing IDH1 inhibitors, ammonia-lowering strategies, or splicing modulators in MASH; provides candidate biomarkers (minor intron retention signatures) to stratify patients and monitor response.
Key Findings
- Minor intron splicing is disrupted in mouse and human MASH, with Insig1/Insig2 intron retention driving proteolytic activation of SREBP1c.
- Disruption triggers IDH1-mediated reductive carboxylation and de novo lipogenesis with hepatic ammonia accumulation that initiates fibrosis.
- Ammonia clearance or IDH1 inhibition blocked hepatic fibrogenesis and mitigated MASH progression.
- Zrsr1 overexpression restored splicing and ameliorated MASH, highlighting minor intron splicing dysfunction as a pathogenic mechanism and therapeutic target.
Methodological Strengths
- Multi-species validation (mouse and human) with concordant mechanisms.
- Causal interventions including genetic rescue (Zrsr1 overexpression) and pharmacologic targeting (IDH1 inhibition, ammonia clearance).
Limitations
- Primarily preclinical; human interventional validation is pending.
- Specificity and safety of targeting minor intron splicing or IDH1 in humans remain to be established.
Future Directions: Validate intron retention signatures and ammonia/IDH1 axes as biomarkers/targets in prospective human cohorts; test combinatorial therapies (IDH1 inhibition plus ammonia-lowering) and define patient subsets most likely to benefit.
2. Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.
Across 94 SDHB-mutant PCPG, sympathetic vs parasympathetic tumors show distinct cell-of-origin molecular programs. TERT and ATRX alterations mark metastatic disease with increased mutation load and telomeric/transcriptional features. Two acquired resistance mechanisms to alkylating chemotherapy were identified: MGMT overexpression and mismatch repair deficiency with hypermutation.
Impact: Provides clinically actionable biomarkers (TERT/ATRX) for metastasis risk and uncovers resistance mechanisms (MGMT, MMR deficiency) that can inform therapy selection and trial design in SDHB-mutant PCPG.
Clinical Implications: Support routine testing of TERT/ATRX in SDHB-mutant PCPG to stratify metastasis risk; consider MGMT expression and MMR status when selecting alkylating agents or immunotherapy, and for clinical trial eligibility.
Key Findings
- Sympathetic vs parasympathetic SDHB-mutant PCPG show distinct molecular profiles reflecting cell-of-origin.
- TERT and ATRX alterations are associated with metastatic PCPG, with higher mutation loads and specific telomeric/transcriptional signatures.
- Most tumors have quiet genomes with occasional cooperative drivers (e.g., EPAS1/HIF-2α).
- Two resistance mechanisms to alkylating chemotherapy were identified: MGMT overexpression and mismatch repair deficiency causing hypermutation.
Methodological Strengths
- Comprehensive multi-omic profiling across 94 tumors using seven molecular methods.
- Clinically oriented analyses linking genomic alterations to metastasis and treatment resistance.
Limitations
- Observational design; lacks prospective clinical validation of biomarker-guided decisions.
- Sample size is substantial for a rare tumor but still limits subgroup analyses.
Future Directions: Prospectively validate TERT/ATRX, MGMT, and MMR status as predictive/prognostic markers; explore tailored regimens (e.g., MGMT-low alkylator sensitivity, MMR-deficient immunotherapy) and integrate multi-omic signatures into risk models.
3. Absence of the intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.
Genetic deletion of G0S2 abolishes diet-induced hypertriglyceridemia and attenuates atherogenesis by enhancing whole-body triglyceride clearance via increased LPL concentration/activity from white adipose tissue. WAT transplantation from G0S2-deficient mice normalizes plasma TG in hypertriglyceridemic mice, suggesting adipocyte G0S2 as a drug target to coordinate intracellular and intravascular lipolysis.
Impact: Identifies adipocyte G0S2 as a nodal regulator linking intracellular ATGL activity to systemic LPL-mediated TG clearance with strong translational potential for hypertriglyceridemia and atherosclerosis.
Clinical Implications: Pharmacologic inhibition of G0S2, or strategies that enhance adipose LPL stability/activity, could offer a novel approach to rapidly lower triglycerides and reduce atherosclerotic risk.
Key Findings
- G0S2 deletion in mice abolishes diet-induced hypertriglyceridemia and reduces atherogenesis by enhancing whole-body TG clearance.
- Increased circulating LPL concentration/activity originates predominantly from white adipose tissue; WAT transplantation from G0S2-deficient mice normalizes plasma TG.
- Absence of G0S2 improves insulin sensitivity, decreases ANGPTL4, and stabilizes adipocyte LPL protein; effects reversed by ATGL inhibition.
Methodological Strengths
- Genetic loss-of-function with phenotypic rescue via tissue transplantation.
- Mechanistic linkage of intracellular (ATGL) and intravascular (LPL) lipolysis with multiple functional readouts (TG clearance, atherogenesis, insulin sensitivity).
Limitations
- Preclinical murine data; human validation of efficacy/safety for targeting G0S2 is needed.
- Potential off-target metabolic effects and long-term consequences of modulating adipose lipolysis remain to be assessed.
Future Directions: Develop specific G0S2 inhibitors and assess triglyceride-lowering efficacy and vascular outcomes in relevant large-animal models; explore patient subsets with severe hypertriglyceridemia for early clinical translation.