Weekly Endocrinology Research Analysis
This week’s endocrinology literature emphasized mechanistic insights that open translational paths: an endothelial ER‑stress checkpoint (IRE1α→THBS1) was shown to enable adaptive islet vascularization and insulin secretion under metabolic stress; a mitochondrial carrier (SLC25A45) governing carnitine biosynthesis and fuel switching was identified; and a liver GPCR (GPR110) coupled to ERα explains a female-biased susceptibility to MASH. Collectively these studies prioritize vascular, mitochondria
Summary
This week’s endocrinology literature emphasized mechanistic insights that open translational paths: an endothelial ER‑stress checkpoint (IRE1α→THBS1) was shown to enable adaptive islet vascularization and insulin secretion under metabolic stress; a mitochondrial carrier (SLC25A45) governing carnitine biosynthesis and fuel switching was identified; and a liver GPCR (GPR110) coupled to ERα explains a female-biased susceptibility to MASH. Collectively these studies prioritize vascular, mitochondrial, and sex-specific targets for metabolic disease therapeutics and biomarker development.
Selected Articles
1. Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets.
Endothelial‑specific IRE1α deletion in high‑fat diet mice caused glucose intolerance with impaired insulin secretion, linked to blunted intra‑islet angiogenesis and islet growth. Mechanistically, IRE1α RNase activity degrades THBS1 mRNA in islet endothelium, relieving anti‑angiogenic pressure and enabling adaptive vascular support of β‑cell function.
Impact: Reveals an endothelial ER‑stress checkpoint that links vascular regulation to endocrine adaptation in obesity — a new conceptual axis connecting vascular biology and β‑cell resilience with translational targetability.
Clinical Implications: Modulating the endothelial IRE1α–THBS1 axis could be explored to enhance islet revascularization and β‑cell function in obesity and diabetes, suggesting vascular‑focused adjuncts to metabolic therapies.
Key Findings
- Endothelial IRE1α deletion in high‑fat diet mice caused glucose intolerance and impaired insulin secretion.
- Loss of endothelial IRE1α blunted intra‑islet angiogenesis and compensatory islet growth without affecting adiposity.
- IRE1α RNase activity mediates THBS1 mRNA decay in islet endothelium, relieving anti‑angiogenic signaling.
2. Mitochondrial control of fuel switching via carnitine biosynthesis.
SLC25A45 was identified as the mitochondrial trimethyllysine carrier essential for carnitine biosynthesis. Loss of SLC25A45 depletes cellular carnitine pools, impairs mitochondrial fatty acid oxidation, and shifts cellular metabolism toward carbohydrate reliance, revealing a core mechanism of fuel flexibility.
Impact: Identifying a previously unrecognized mitochondrial transporter that controls carnitine pools and fatty‑acid oxidation is a fundamental advance with implications for metabolic adaptation, carnitine deficiency states, and diet‑related interventions.
Clinical Implications: Modulating SLC25A45 or downstream carnitine biosynthesis may offer strategies to correct fatty‑acid oxidation defects or to optimize metabolic flexibility in disease or dietary contexts, warranting human genetic and translational studies.
Key Findings
- SLC25A45 functions as the mitochondrial trimethyllysine carrier enabling carnitine biosynthesis.
- Deficiency of SLC25A45 reduced cellular carnitine pools and impaired mitochondrial fatty acid oxidation.
- Loss of SLC25A45 caused a metabolic shift toward carbohydrate utilization.
3. Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.
Hepatocyte‑specific Gpr110 knockout protected female but not male mice from diet‑induced MASH; a human GPR110 variant (rs937057 T>C) associated with higher MASLD prevalence in women. The protective phenotype depended on hepatic ERα, defining a sex‑specific GPCR–ERα axis in MASH pathogenesis.
Impact: Defines a sex‑specific, druggable hepatic GPCR mechanism with human genetic support, enabling precision approaches that account for sex in MASH treatment and risk stratification.
Clinical Implications: GPR110 (and its ERα dependence) may be developed as a female‑targeted therapeutic or biomarker for MASH; genotyping could inform sex‑specific risk stratification pending replication.
Key Findings
- Hepatocyte‑specific Gpr110 deletion protected female, but not male, mice from MASH.
- Human GPR110 variant rs937057 T>C associated with higher MASLD prevalence in women.
- Protective effects in female mice were abrogated by hepatic ERα knockdown, indicating ERα dependence.