Daily Endocrinology Research Analysis
Analyzed 81 papers and selected 3 impactful papers.
Summary
Analyzed 81 papers and selected 3 impactful articles.
Selected Articles
1. HDI-STARR-seq Identifies Functional GH-regulated Sex-Biased Hepatocyte Enhancers Linked to Liver Metabolism and Disease.
Using an in vivo HDI-STARR-seq library integrated with single-nucleus multiomics, the authors validated hundreds of GH-regulated, sex-biased hepatocyte enhancers whose activities mirror chromatin accessibility and histone marks. Motif analyses implicated STAT5-axis repressors (BCL6, CUX2) and HNF4A, and enhancer-gene links mapped to MASLD-enabling and -protective loci, offering a mechanistic substrate for sex-differential MASLD susceptibility.
Impact: Introduces an in vivo, high-throughput enhancer functionalization strategy in intact liver to decode GH- and sex-dependent regulatory architecture linked to metabolic liver disease risk.
Clinical Implications: Enables sex-aware risk stratification and points to GH-STAT5-BCL6/CUX2/HNF4A-centered enhancer networks as candidate targets for MASLD-modifying interventions.
Key Findings
- Constructed a 23,912-reporter HDI-STARR-seq library spanning 1,839 liver ATAC regions; 840 regions showed sex-biased and/or GH-regulated enhancer activity in vivo.
- Regulated enhancers were enriched for active histone marks (H3K27ac, H3K4me1) and for binding sites of BCL6 and CUX2; STAT5 binding was broadly enriched.
- Enhancers were linked to both MASLD-enabling and MASLD-protective genes, providing a mechanistic basis for sex differences in MASLD susceptibility.
Methodological Strengths
- Integration of single-nucleus chromatin accessibility profiling with in vivo high-throughput enhancer functional assays.
- Physiological liver context via hydrodynamic delivery, with enhancer activity mirroring endogenous chromatin and histone marks.
Limitations
- Mouse-based study; human liver validation and direct clinical translation remain to be established.
- Enhancer–gene links were largely inferred; causal perturbation at individual enhancers was not systematically performed.
Future Directions: Apply CRISPRi/CRISPRa or base editing to perturb prioritized enhancers in vivo; extend mapping to human liver and evaluate pharmacologic modulation of GH–STAT5 pathways in sex-informed MASLD therapy.
Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin access
2. β-Hydroxybutyrate upregulates hepatic histone β-hydroxybutyrylation modification, promotes the expression of PPARα, and alleviates the hepatic steatosis in MASLD.
In db/db mice and PA-treated AML12 hepatocytes, β-hydroxybutyrate reduced hepatic lipid accumulation while increasing PPARα and downstream fatty acid oxidation genes. BHB elevated total Kbhb and H3K9bhb; pharmacologic blockade of Kbhb (p300 inhibitor A485 or ACSS2 inhibition) blunted PPARα induction, supporting histone β-hydroxybutyrylation as a mechanistic mediator.
Impact: Links a physiologic metabolite (BHB) to an epigenetic mark (histone Kbhb) that drives PPARα-dependent lipid oxidation, offering a tractable mechanism to modulate MASLD.
Clinical Implications: Supports exploration of dietary/ketogenic strategies or exogenous ketones to enhance hepatic β-oxidation via epigenetic mechanisms; highlights p300/ACSS2-Kbhb axis as a therapeutic target in MASLD.
Key Findings
- BHB reduced hepatic lipid accumulation in db/db mice and in PA-induced AML12 hepatocytes.
- BHB increased PPARα and downstream lipid oxidation gene expression alongside elevated total Kbhb and H3K9bhb.
- Blocking Kbhb with A485 (p300 inhibitor) or ACSS2 inhibition suppressed PPARα induction, implicating histone β-hydroxybutyrylation as causal.
Methodological Strengths
- Convergent in vivo (db/db mice) and in vitro (AML12) models with consistent outcomes.
- Mechanistic testing through targeted pharmacologic inhibition of Kbhb writers to probe causality.
Limitations
- Preclinical study without human validation; translational dosing and safety of BHB/ketosis not addressed.
- Potential off-target effects of epigenetic inhibitors; duration of intervention was short.
Future Directions: Validate Kbhb–PPARα axis in human liver tissue and clinical MASLD; test dietary or pharmacologic strategies to safely induce hepatic Kbhb and improve steatosis.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) stands as the most widespread chronic liver disorder globally. Histone β-hydroxybutyrylation (Kbhb)-a novel post-translational modification of histones driven by β-hydroxybutyrate (BHB)-has recently been recognized as a key epigenetic modulator. Our study aimed to explore how BHB influences the expression of hepatic lipid metabolism-associated genes in MASLD, and to determine whether histone Kbhb acts as the mechanistic mediator underlying these effects. METHODS: For in vivo experiments, db/db mice fed a high-fat diet were utilized as the MASLD model. Following BHB intervention, changes in glycolipid metabolism and lipid accumulation in liver were assessed. Hepatic expression of lipid oxidation-related genes (e.g., PPARα) was quantified via qPCR; hepatic Pan-Kbhb and H3K9bhb levels were detected using immunohistochemistry and immunofluorescence. For in vitro experiments, a palmitic acid (PA)-induced AML12 hepatocyte model was established. After BHB treatment, intracellular lipid accumulation was visualized via Oil Red O and BODIPY staining; PPARα and downstream lipid oxidation gene expression was measured by qPCR and Western blotting. Total protein and histone Kbhb were evaluated using immunofluorescence and Western blotting. RESULTS: BHB effectively mitigated lipid accumulation in the livers of db/db mice and PA-induced AML12 cells, while upregulating PPARα and its downstream lipid oxidation-related target genes. Simultaneously, BHB elevated total protein Kbhb and histone H3K9bhb modifications in hepatic cells. Critically, blocking Kbhb (via A485, an inhibitor of the acyltransferase P300, or an acyl-CoA synthetase 2 inhibitor) led to significant downregulation of PPARα and its target gene expression. CONCLUSION: BHB alleviates lipid accumulation in the liver of MASLD by promoting the expression of PPARα and its downstream lipid oxidation-related genes in the hepatocytes, which is associated with histone Kbhb modification.
3. Patients with MASLD Exhibit In Vivo Changes in Hepatic Response to Oral Fructose Consumption.
In 37 non-diabetic overweight/obese adults, oral fructose elicited rapid hepatic PME increases, early Pi dips followed by rebound, and sustained ATP reductions in participants without MASLD, whereas MASLD participants showed blunted PME responses, delayed Pi increases, and transient/non-significant ATP changes. These 31P-MRS signatures indicate altered hepatic fructose handling in MASLD.
Impact: Provides noninvasive, in vivo metabolic evidence that hepatic phosphate metabolite dynamics after fructose are altered in MASLD, refining pathophysiologic understanding and potential biomarkers.
Clinical Implications: Suggests that dynamic 31P-MRS responses to fructose could serve as functional biomarkers of hepatic metabolic flexibility in MASLD and inform dietary counseling regarding fructose intake.
Key Findings
- At baseline, hepatic ATP, PME, and PDE did not differ between MASLD and non-MASLD groups.
- After 75 g oral fructose, non-MASLD participants showed rapid PME increases, early Pi decreases with rebound above baseline, and sustained ATP reductions.
- Participants with MASLD exhibited blunted PME response, delayed Pi increase (at ~45 minutes), and non-significant/brief ATP changes, indicating altered fructose handling.
Methodological Strengths
- Within-subject, time-resolved 31P-MRS capturing dynamic hepatic phosphate metabolites after standardized fructose challenge.
- Complementary 1H-MRS liver fat quantification and OGTT characterization in a well-phenotyped cohort.
Limitations
- Small sample size and short observation window (60 minutes) limit generalizability and mechanistic resolution.
- No direct measurement of hepatic enzymatic fluxes or concurrent tissue biopsy validation.
Future Directions: Expand to larger cohorts with simultaneous 13C/31P spectroscopy, assess dietary fructose modulation, and correlate dynamic MRS metrics with histology and clinical outcomes.
OBJECTIVE: This study compared in vivo changes in hepatic phosphate metabolites using phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with vs. without MASLD after fructose consumption. METHODS: Thirty-seven overweight or obese patients without diabetes underwent: a 2-hour oral glucose tolerance test, a fasting liver proton magnetic resonance spectroscopy (1H-MRS), and a 31P-MRS before and during 60 minutes after an oral 75-gram fructose challenge. RESULTS: Before fructose consumption, there were no differences in ATP, phosphomonoesters (PME) or phosphodiesters (PDE) between groups. After fructose, patients without MASLD had a rapid increase in PME (from 15.5±4.8 to 19.3±5.1 within 15 minutes, p=0.033). In these patients, inorganic phosphate decreased during the first 30 minutes but then increased leading to higher than basal levels (from 10.2±1.9 to 11.8±2.8, p=0.037). ATP significantly dropped in patients without MASLD within 15 minutes (from 21.8±3.4 to 19.9±4.0, p=0.018), with persistently lower levels after 60 minutes (19.1±4.1, p=0.006 vs. baseline). However, all these responses to oral fructose appeared blunted in patients with MASLD, with unchanged PME levels and only showing an inorganic phosphate increase 45 minutes after fructose consumption. ATP levels showed a non-significant drop in the first 15 minutes with recovery of baseline levels at minute 30. CONCLUSIONS: Following fructose consumption, patients with MASLD exhibited distinct patterns of change in phosphate metabolites, reflecting differences in hepatic metabolic responses. These findings suggest altered hepatic metabolic handling of fructose in MASLD, which may have implications for disease progression.