Daily Endocrinology Research Analysis
Analyzed 99 papers and selected 3 impactful papers.
Summary
Three impactful metabolism/endocrinology papers stood out today. A Science study identifies SLC25A45 as the mitochondrial trimethyllysine carrier essential for carnitine biosynthesis and fuel switching. Translational work in Cell Metabolism shows dual ACLY/ACSS2 inhibition (EVT0185) reduces steatosis and fibrosis via stellate-cell pathway modulation, while a large Nature Communications cohort links higher exposure to multiple preservative additives with increased type 2 diabetes risk.
Research Themes
- Mitochondrial metabolite transport and fuel selection
- Therapeutic targeting of acetyl-CoA sources in steatohepatitis/fibrosis
- Dietary preservative exposures and type 2 diabetes risk
Selected Articles
1. Mitochondrial control of fuel switching via carnitine biosynthesis.
This mechanistic study identifies SLC25A45 as the mitochondrial trimethyllysine carrier required for carnitine biosynthesis, thereby enabling mitochondrial fatty acid oxidation and fuel switching. Loss of SLC25A45 depletes carnitine and impairs fatty acid oxidation, shifting metabolism toward carbohydrate usage.
Impact: Revealing a previously unrecognized mitochondrial carrier that governs carnitine biosynthesis provides a fundamental advance in metabolic flexibility and nutrient adaptation biology.
Clinical Implications: Modulating SLC25A45-carnitine pathways could inform strategies for metabolic disorders, carnitine deficiency, and dietary adaptations (e.g., plant-based diets) where fatty acid oxidation capacity is critical.
Key Findings
- SLC25A45 was identified as the mitochondrial carrier for trimethyllysine, enabling carnitine biosynthesis.
- SLC25A45 deficiency reduced the cellular carnitine pool and impaired mitochondrial fatty acid oxidation.
- Metabolic fuel use shifted toward carbohydrates when SLC25A45 was deficient.
Methodological Strengths
- Discovery of a transporter with clear functional consequences on carnitine pools and fatty acid oxidation
- Mechanistic linkage between mitochondrial metabolite transport and whole-cell fuel selection
Limitations
- Preclinical mechanistic work; human genetic/clinical validation is needed
- Quantitative physiological impacts across tissues and dietary contexts require further study
Future Directions: Validate SLC25A45 variants in humans; assess therapeutic modulation of carnitine biosynthesis in metabolic disease and in dietary adaptation states.
Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism.
2. Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
EVT0185, a dual ACLY/ACSS2 inhibitor, lowers hepatic and serum triglycerides, improves insulin resistance, and attenuates fibrosis by suppressing hepatic stellate cell activation. Multi-omics and human tissue data implicate inhibition of acetate (ACSS2) and cholesterol metabolism as key mechanisms.
Impact: Demonstrates a targeted metabolic strategy that directly modulates HSC activation and fibrosis, advancing therapeutic development for MASH.
Clinical Implications: Dual ACLY/ACSS2 inhibition could serve as a novel antifibrotic/antilipogenic approach for MASH; findings justify early-phase clinical trials and biomarker development.
Key Findings
- EVT0185 reduced serum and liver triglycerides and improved insulin resistance in mouse MASH models.
- The drug suppressed hepatic stellate cell activation in vivo and in vitro; spatial transcriptomics and scRNA-seq implicated ACSS2-mediated acetate and cholesterol metabolism pathways.
- EVT0185 inhibited de novo lipogenesis in human liver slices and blocked TGFβ1-induced activation of primary human HSCs.
Methodological Strengths
- Multi-system validation: mouse models, human liver slices, and primary human HSCs
- Mechanistic depth with spatial transcriptomics and single-cell RNA sequencing
Limitations
- Preclinical study; no human clinical outcomes yet
- Potential off-target or metabolic compensation effects require evaluation
Future Directions: Conduct phase I/II trials with pharmacodynamic biomarkers (e.g., ACSS2 activity, cholesterol synthesis) and assess antifibrotic efficacy; explore combination with lifestyle or other antifibrotics.
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.
3. Associations between preservative food additives and type 2 diabetes incidence in the NutriNet-Santé prospective cohort.
In 108,723 French adults followed from 2009–2023, higher cumulative exposure to multiple preservative food additives was associated with increased incident type 2 diabetes. Twelve widely used preservatives retained significant associations after multiple testing, supporting reevaluation of their safety and dietary guidance emphasizing minimally processed foods.
Impact: Provides large-scale, exposure-specific epidemiologic evidence linking commonly used preservatives to diabetes incidence, informing regulatory and public health nutrition policy.
Clinical Implications: Clinicians can counsel patients with metabolic risk to minimize preservative-laden ultra-processed foods; findings may prompt screening emphasis in high-exposure individuals and inform policy.
Key Findings
- Among 58 preservatives evaluated, 17 were commonly consumed (≥10%); 13 (12 after multiple-testing correction) were associated with higher T2D incidence.
- Significant associations included potassium sorbate, potassium metabisulfite, sodium nitrite, acetic/citric/phosphoric acids, sodium acetates, calcium propionate, sodium ascorbate, alpha-tocopherol, sodium erythorbate, and rosemary extracts.
- Exposure assessment combined repeated 24h-dietary records with composition databases and targeted laboratory assays; multi-adjusted Cox models used 1,131 incident T2D cases.
Methodological Strengths
- Very large prospective cohort with repeated dietary assessments and additive-specific exposure estimation
- Multi-source exposure ascertainment (databases plus lab assays) and rigorous multi-adjusted Cox modeling
Limitations
- Observational design limits causal inference; residual confounding cannot be excluded
- Exposure misclassification is possible despite detailed assessment
Future Directions: Define exposure thresholds and mechanisms for high-signal preservatives; replicate in diverse cohorts and test policy interventions reducing additive exposures.
Experimental studies suggested potential adverse effects of preservative food additives, but epidemiological data are lacking. We aim to investigate associations between exposure to these compounds and type 2 diabetes incidence in the NutriNet-Santé prospective cohort (n = 108,723; 79.2%women; mean age=42.5 (SD = 14.6); France, 2009-2023). Dietary intakes are assessed using repeated 24h-dietary records. Exposure is evaluated through multiple composition databases and ad-hoc laboratory assays in food matrices. Associations between cumulative exposures to preservatives and diabetes incidence are characterised using multi-adjusted Cox models. The sum of total preservatives encompasses 58 substances. Among those, 17 are consumed by at least 10% of the study population and thus individually investigated. Thirteen (12 after multiple test correction) widely used individual preservatives are associated with higher diabetes incidence (n=1131cases): potassium sorbate, potassium metabisulfite, sodium nitrite, acetic, citric and phosphoric acids, sodium acetates, calcium propionate, sodium ascorbate, alpha-tocopherol, sodium erythorbate, and rosemary extracts. These findings call for their safety re-evaluation and support recommendations to favour fresh and minimally processed foods without superfluous additives. Trial registration: The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644).