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Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury., Competing Interests: Dr Javaheri was supported by R01HL155344 and K08HL138262 from the National Heart, Lung, and Blood Institute and by the Diabetes Research Center at Washington University in St Louis of the National Institutes of Health (NIH) under award number P30DK020579, as well as NIH grant P30DK056341 (Nutrition Obesity Research Center), and by the Children’s Discovery Institute of Washington University (MC-FR-2020-919) and St Louis Children’s Hospital. Dr Guo was supported by an American Heart Association Postdoctoral Fellowship (898679). Dr Diwan was supported by grants from the Department of Veterans Affairs (I01BX004235) and the NIH (HL107594, HL43431, and NS094692). Dr Scherrer-Crosbie is supported by R01HL130539 and R01HL131613. Dr Rawnsley was supported by training grant support from the NIH (T32007081). Dr Desai was supported by R01HL136603. Dr Bergom was supported by R01HL147884. Research reported in this publication was also supported by the National Cancer Institute of the NIH under award numbers R50CA211466 (Dr Rettig), R35CA210084 (Dr DiPersio), P01CA101937 (Dr DiPersio), and R01HL119962 (Dr Parks). Human heart tissue procurement was supported by the National Heart, Lung, and Blood Institute via R01HL105993 (Drs Margulies and Cappola). Drs Christoffersen and Hajny were supported by the Novo Nordisk Foundation (0053008 and NNF13OC0003898). Dr Stitziel was supported in part by R01HL131961, R01HL159171, P01HL151328, and UM1HG008853 and by the Foundation for Barnes-Jewish Hospital. We acknowledge support from the NIH Shared Instrumentation Grant (S10RR027552) for support through the Hope Center Neuroimaging Core, the Molecular Microbiology Imaging Facility, and the Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center (DDRCC NIH P30DK052574) at Washington University School of Medicine. Dr Stitziel has received consulting fees from Sension Therapeutics and investigator-initiated research funding from Regeneron Pharmaceuticals unrelated to the content of this study. Dr Javaheri has a pending patent for fusion protein nanodiscs for the treatment of heart failure and eye diseases, receives research funding from AstraZeneca, and is on the Scientific Advisory Board of Mobius Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Mitochondria are fundamental for life and require balanced ion exchange to maintain proper functioning. The mitochondrial cation exchanger LETM1 sparks interest because of its pathophysiological role in seizures in the Wolf Hirschhorn Syndrome (WHS). Despite observation of sleep disorganization in epileptic WHS patients, and growing studies linking mitochondria and epilepsy to circadian rhythms, LETM1 has not been studied from the chronobiological perspective. Here we established a viable letm1 knock-out, using the diurnal vertebrate Danio rerio to study the metabolic and chronobiological consequences of letm1 deficiency. We report diurnal rhythms of Letm1 protein levels in wild-type fish. We show that mitochondrial nucleotide metabolism is deregulated in letm1-/- mutant fish, the rate-limiting enzyme of NAD + production is up-regulated, while NAD + and NADH pools are reduced. These changes were associated with increased expression amplitude of circadian core clock genes in letm1-/- compared with wild-type under light/dark conditions, suggesting decreased NAD(H) levels as a possible mechanism for circadian system perturbation in Letm1 deficiency. Replenishing NAD pool may ameliorate WHS-associated sleep and neurological disorders., (© 2022 Dao et al.)

Objective: Apolipoprotein M (apoM) is an essential transporter of plasma Sphingosine-1-Phosphate (S1P), typically attached to all lipoprotein classes, but with a majority bound to high density lipoproteins (HDL). ApoM-deficient mice display an increased activity in brown adipose tissue and a concomitant fast turnover of triglycerides. In what manner apoM/S1P affect the triglyceride metabolism is however still unknown and explored in the present study., Methods: Triglyceride turnover and potentially associated metabolic pathways were studied in the female human apoM transgenic mouse model (apoM-Tg) with increased plasma apoM and S1P levels. The model was compared with wild type (WT) mice., Results: ApoM-Tg mice had a reduced plasma triglyceride turnover rate and a lower free fatty acid uptake in subcutaneous adipocytes compared to WT mice. Screening for potential molecular mechanisms furthermore revealed a reduction in plasma lipase activity in apoM-Tg animals. Overexpression of apoM also reduced the plasma levels of fibroblast growth factor 21 (FGF21)., Conclusions: The study features the significant role of the apoM/S1P axis in maintaining a balanced triglyceride metabolism. Further, it also highlights the risk of inducing dyslipidaemia in patients receiving S1P-analouges and additionlly emphasizes the apoM/S1P axis as a potential therapeutic target in treatment of hypertriglyceridemia., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Recent studies have discovered a role of apolipoprotein M (apoM) in energy metabolism, and observational analyses in humans suggest an association with type 2 diabetes. The causal relationship remains however elusive., Objective: To investigate whether reduced plasma apoM concentrations are causally linked to increased risk of type 2 diabetes., Design: Prospective study design analyzed by Mendelian randomization., Setting and Participants: Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants from the CCHS with available plasma apoM (n = 725). Genetic analyses included the complete cohorts (n = 102 446). During a median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes., Main Outcome Measures: Plasma apoM concentration, genetic variants in APOM, and type 2 diabetes., Results: First, we identified an inverse correlation between plasma apoM and risk of type 2 diabetes in a subset of participants from the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polymorphisms in APOM further revealed a 10.8% (P = 6.2 × 10-5) reduced plasma apoM concentration in participants with variant rs1266078. Third, a meta-analysis including data from 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes., Conclusions: The present study does not appear to support a causal association between plasma apoM and risk of type 2 diabetes., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sphingosine-1-phosphate (S1P) is a bioactive lipid implicated in e.g. angiogenesis, lymphocyte trafficking, and endothelial barrier function. Erythrocytes are a main source of plasma S1P together with platelets and endothelial cells. Apolipoprotein M (apoM) in HDL carries 70% of plasma S1P, whereas 30% is carried by albumin. The current aim was to investigate the role of apoM in export of S1P from human erythrocytes. Erythrocytes exported S1P more efficiently to HDL than to albumin, particularly when apoM was present in HDL. In contrast, export of sphingosine to HDL was unaffected by the presence of apoM. The specific ability of apoM to promote export of S1P was independent of apoM being bound in HDL particles. Treatment with MK-571, an inhibitor of the ABCC1 transporter, effectively reduced export of S1P from human erythrocytes to apoM, whereas the export was unaffected by inhibitors of ABCB1 or ATPase. Thus, ABCC1 could be involved in export of S1P from erythrocytes to apoM.

Hepatocytes, renal proximal tubule cells as well as the highly specialized endothelium of the blood brain barrier (BBB) express and secrete apolipoprotein M (apoM). ApoM is a typical lipocalin containing a hydrophobic binding pocket predominantly carrying Sphingosine-1-Phosphate (S1P). The small signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss. Finally, polarized endothelial cells constituting the lining of the BBB express apoM and secrete the protein to the brain as well as to the blood compartment. The review will provide novel insights on apoM and S1P, and its role in hepatic fibrosis, neuroinflammation and BBB integrity., Competing Interests: The authors declare no conflict of interest.