bims-mimcad 2024-09-08 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–09–08
eleven papers selected by
Henver Brunetta, Karolinska Institutet

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program.
Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.
Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program.
Dietary Protein Defends Lean Mass and Maintains the Metabolic Benefits of Glucagon Receptor Agonism in Mice.
Upstream alternative polyadenylation in SCN5A produces a short transcript isoform encoding a mitochondria-localized NaV1.5 N-terminal fragment that influences cardiomyocyte respiration.
Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity.
Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.
Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.
The epicardial adipose tissue confined in the atrioventricular groove can be used to assess atrial adipose tissue and atrial dysfunction in cardiac magnetic resonance imaging.
Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.

J Am Coll Cardiol. 2024 Aug 29. pii: S0735-1097(24)08195-6. [Epub ahead of print]

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program.

STEP-HFpEF and STEP-HFpEF DM Investigators

   BACKGROUND: Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined.
OBJECTIVES: The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program.
METHODS: This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF.
RESULTS: Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history.
CONCLUSIONS: In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline.(Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470]).

Keywords:  KCCQ-CSS; atrial fibrillation; heart failure with preserved ejection fraction; obesity; patient-reported outcomes; semaglutide

DOI:  https://doi.org/10.1016/j.jacc.2024.08.023
J Am Coll Cardiol. 2024 Aug 29. pii: S0735-1097(24)08192-0. [Epub ahead of print]

Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.

STEP-HFpEF Trial Committees and Investigators

   BACKGROUND: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown.
OBJECTIVES: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function.
METHODS: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values.
RESULTS: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area.
CONCLUSIONS: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).

Keywords:  cardiac remodeling; echocardiography; glucagon-like peptide-1 receptor agonists; heart failure; heart failure with preserved ejection fraction; obesity

DOI:  https://doi.org/10.1016/j.jacc.2024.08.021
J Am Coll Cardiol. 2024 Aug 28. pii: S0735-1097(24)08234-2. [Epub ahead of print]

Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program.

STEP-HFpEF Trial Committees and Investigators

   BACKGROUND: Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined.
OBJECTIVES: This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program.
METHODS: This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L).
RESULTS: In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91).
CONCLUSIONS: Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).

Keywords:  heart failure with preserved ejection fraction; inflammation; semaglutide

DOI:  https://doi.org/10.1016/j.jacc.2024.08.028
Mol Metab. 2024 Sep 03. pii: S2212-8778(24)00155-8. [Epub ahead of print] 102024

Dietary Protein Defends Lean Mass and Maintains the Metabolic Benefits of Glucagon Receptor Agonism in Mice.

Tatiana Lopes, David C D Hope, Jose M Ramos-Pittol, Anna Curtis, Jed Shrewsbury, Iona Davies, Zijing Zhou, Alessandro Sardini, James S Minnion, Dirk Dormann, Gavin Bewick, Keving G Murphy, David Carling, Stephen R Bloom, Tricia M M Tan, Bryn M Owen.

   OBJECTIVE: - Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass.
METHODS: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation.
RESULTS: - Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved.
CONCLUSION: - Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

Keywords:  Drug; Glucagon; Lean mass; MAFLD; Muscle mass; Obesity; Side-effect

DOI:  https://doi.org/10.1016/j.molmet.2024.102024
bioRxiv. 2024 Aug 10. pii: 2024.08.09.607406. [Epub ahead of print]

Upstream alternative polyadenylation in SCN5A produces a short transcript isoform encoding a mitochondria-localized NaV1.5 N-terminal fragment that influences cardiomyocyte respiration.

Nathan H Witmer, Jared M McLendon, Colleen S Stein, Jin-Young Yoon, Elena Berezhnaya, John W Elrod, Barry L London, Ryan L Boudreau.

SCN5A encodes the cardiac voltage-gated Na+ channel, NaV1.5, that initiates action potentials. SCN5A gene variants cause arrhythmias and increased heart failure risk. Mechanisms controlling NaV1.5 expression and activity are not fully understood. We recently found a well-conserved alternative polyadenylation (APA) signal downstream of the first SCN5A coding exon. This yields a SCN5A-short transcript isoform expressed in several species (e.g. human, pig, and cat), though rodents lack this upstream APA. Reanalysis of transcriptome-wide cardiac APA-seq and mRNA-seq data shows reductions in both upstream APA usage and short/full-length SCN5A mRNA ratios in failing hearts. Knock-in of the human SCN5A APA sequence into mice is sufficient to enable expression of SCN5A -short transcript, while significantly decreasing expression of full-length SCN5A mRNA. Notably, SCN5A -short transcript encodes a novel protein (NaV1.5-NT), composed of an N-terminus identical to NaV1.5 and a unique C-terminus derived from intronic sequence. AAV9 constructs were able to achieve stable NaV1.5-NT expression in mouse hearts, and western blot of human heart tissues showed bands co-migrating with NaV1.5-NT transgene-derived bands. NaV1.5-NT is predicted to contain a mitochondrial targeting sequence and localizes to mitochondria in cultured cardiomyocytes and in mouse hearts. NaV1.5-NT expression in cardiomyocytes led to elevations in basal oxygen consumption rate, ATP production, and mitochondrial ROS, while depleting NADH supply. Native PAGE analyses of mitochondria lysates revealed that NaV1.5-NT expression resulted in increased levels of disassembled complex V subunits and accumulation of complex I-containing supercomplexes. Overall, we discovered that APA-mediated regulation of SCN5A produces a short transcript encoding NaV1.5-NT. Our data support that NaV1.5-NT plays a multifaceted role in influencing mitochondrial physiology: 1) by increasing basal respiration likely through promoting complex V conformations that enhance proton leak, and 2) by increasing overall respiratory efficiency and NADH consumption by enhancing formation and/or stability of complex I-containing respiratory supercomplexes, though the specific molecular mechanisms underlying each of these remain unresolved.

DOI: https://doi.org/10.1101/2024.08.09.607406
J Hepatol. 2024 Aug 30. pii: S0168-8278(24)02490-5. [Epub ahead of print]

Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity.

Sabine Kahl, Klaus Straßburger, Giovanni Pacini, Nina Trinks, Kalliopi Pafili, Lucia Mastrototaro, Bedair Dewidar, Theresia Sarabhai, Sandra Trenkamp, Irene Esposito, Matthias Schlensak, Frank A Granderath, Michael Roden.

   BACKGROUND & AIMS: Hepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic OXPHOS capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases.
METHODS: We analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples.
RESULTS: Prediabetes was present in 30 participants, and MASLD in 46 participants. Thereof, 25 had metabolic dysfunction-associated steatohepatitis (MASH), and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD related to higher biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance.
CONCLUSIONS: Rising liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance. CLINTRIALS.
GOV IDENTIFIER: NCT01477957.

Keywords:  Energy metabolism; grade 3 obesity; impaired fasting glucose; impaired glucose tolerance; steatosis

DOI:  https://doi.org/10.1016/j.jhep.2024.08.012
Nat Commun. 2024 Sep 03. 15(1): 7677

Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.

Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

DOI: https://doi.org/10.1038/s41467-024-50632-2
iScience. 2024 Sep 20. 27(9): 110633

Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.

Bo Guo, Fujiao Zhang, Yue Yin, Xingmin Ning, Zihui Zhang, Qinglei Meng, Ziqi Yang, Wenhua Jiang, Manling Liu, Yishi Wang, Lijuan Sun, Lu Yu, Nan Mu.

  Pyruvate dehydrogenase complex (PDC) is a crucial enzyme that connects glycolysis and the tricarboxylic acid (TCA) cycle pathway. It plays an essential role in regulating glucose metabolism for energy production by catalyzing the oxidative decarboxylation of pyruvate to acetyl coenzyme A. Importantly, the activity of PDC is regulated through post-translational modifications (PTMs), phosphorylation, acetylation, and O-GlcNAcylation. These PTMs have significant effects on PDC activity under both physiological and pathophysiological conditions, making them potential targets for metabolism-related diseases. This review specifically focuses on the PTMs of PDC in cardiovascular diseases (CVDs) such as myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, obesity-related cardiomyopathy, heart failure (HF), and vascular diseases. The findings from this review offer theoretical references for the diagnosis, treatment, and prognosis of CVD.

Keywords:  Biochemistry; Cardiovascular medicine; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110633
Endocrinology. 2024 Sep 05. pii: bqae118. [Epub ahead of print]

Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.

Kamila Roszczyc-Owsiejczuk, Piotr Zabielski, Monika Imierska, Karolina Pogodzińska, Patrycja Sadowska, Agnieszka Błachnio-Zabielska.

   OBJECTIVE: Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver.
METHODS: In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice.
RESULTS: Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis.
CONCLUSION: Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.

Keywords:  CerS2; CerS4; ceramide; high-fat diet; insulin resistance

DOI:  https://doi.org/10.1210/endocr/bqae118
Eur Heart J Imaging Methods Pract. 2024 Jan;2(1): qyae057

The epicardial adipose tissue confined in the atrioventricular groove can be used to assess atrial adipose tissue and atrial dysfunction in cardiac magnetic resonance imaging.

Jonathan Bialobroda, Khaoula Bouazizi, Maharajah Ponnaiah, Nadjia Kachenoura, Etienne Charpentier, Mohamed Zarai, Karine Clement, Fabrizio Andreelli, Judith Aron-Wisnewsky, Stéphane N Hatem, Alban Redheuil.

   Aims: The growing interest in epicardial adipose tissue (EAT) as a biomarker of atrial fibrillation is limited by the difficulties in isolating EAT from other paracardial adipose tissues. We tested the feasibility and value of measuring the pure EAT contained in the atrioventricular groove (GEAT) using cardiovascular magnetic resonance (CMR) imaging in patients with distinct metabolic disorders.
Methods and results: CMR was performed on 100 patients from the MetaCardis cohort: obese (n = 18), metabolic syndrome (MSD) (n = 25), type-2 diabetes (T2D) (n = 42), and age- and gender-matched healthy controls (n = 15). GEAT volume measured from long-axis views was obtained in all patients with a strong correlation between GEAT and atrial EAT (r = 0.95; P < 0.0001). GEAT volume was higher in the three groups of patients with metabolic disorders and highest in the MSD group compared with controls. GEAT volume, as well as body mass and body fat, allowed obese, T2D, and MSD patients to be distinguished from controls. GEAT T1 relaxation and peak longitudinal left atrial (LA) strain in CMR were decreased in T2D patients. Logistic regression and random forest machine learning methods were used to create an algorithm combining GEAT volume, GEAT T1, and peak LA strain to identify T2D patients from other groups with an area under curve (AUC) of 0.81 (Se: 77%, Spe: 80%; 95% confidence interval 0.72-0.91, P < 0.0001).
Conclusion: Atrioventricular groove adipose tissue characteristics measured during routine CMR can be used as a proxy of atrial EAT and integrated in a multi-parametric CMR biomarker for early identification of atrial cardiomyopathy.

Keywords:  atrial cardiomyopathy; cardiometabolism; epicardial adipose tissue; left atrial strain; magnetic resonance imaging CMR

DOI:  https://doi.org/10.1093/ehjimp/qyae057
J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740

Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.

Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.

  Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.

Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model

DOI:  https://doi.org/10.1016/j.jbc.2024.107740