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Sphingolipids (SLs) are chemically diverse lipids that have important structural and signaling functions within mammalian cells. SLs are commonly defined by the presence of a long-chain base (LCB) that is normally formed by the conjugation of L-serine and palmitoyl-CoA. This pyridoxal 5-phosphate (PLP)-dependent reaction is mediated by the enzyme serine-palmitoyltransferase (SPT). However, SPT can also metabolize other acyl-CoAs, in the range of C14 to C18, forming a variety of LCBs that differ by structure and function. Mammalian SPT consists of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to certain tissues only. The influence of the individual subunits on enzyme activity is not clear. Using cell models deficient in SPTLC1, SPTLC2, and SPTLC3, we investigated the role of each subunit on enzyme activity and the LCB product spectrum. We showed that SPTLC1 is essential for activity, whereas SPTLC2 and SPTLC3 are partly redundant but differ in their enzymatic properties. SPTLC1 in combination with SPTLC2 specifically formed C18, C19, and C20 LCBs while the combination of SPTLC1 and SPTLC3 yielded a broader product spectrum. We identified anteiso-branched-C18 SO (meC18SO) as the primary product of the SPTLC3 reaction. The meC18SO was synthesized from anteiso-methyl-palmitate, in turn synthesized from a precursor metabolite generated in the isoleucine catabolic pathway. The meC18SO is metabolized to ceramides and complex SLs and is a constituent of human low- and high-density lipoproteins.

Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems. Not applicable. Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases. Here, they show that Very-long-chain 1-deoxyceramides impair mitochondrial function and cause toxicity. Inhibiting ELOVL1 prevents these effects, suggesting a therapeutic strategy for disorders linked to elevated 1-deoxysphingolipid levels.

High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.

Iron deficiency anemia in the perioperative setting is treated predominantly with intravenous iron formulation, of which ferric carboxymaltose may induce hypophosphatemia by modulating fibroblast growth factor 23. In this single-center, prospective, randomized, double-blind trial, we consented 92 adult patients scheduled for elective major abdominal or thoracic surgery. These patients either had isolated iron deficiency (plasma ferritin <100 ng/mL or transferrin saturation < 20 %) or iron deficiency anemia (hemoglobin (Hb) 100–130 g/L with plasma ferritin <100 ng/mL or transferrin saturation < 20 %). Preoperatively, participants received a single preoperative intravenous dose of ferric carboxymaltose and were then randomly assigned to receive either phosphate or placebo, administered orally three times a day for 30 days corresponding to an 18 mmol dose of daily phosphate supplementation in the intervention group. The primary endpoint was the minimum serum phosphate concentration during follow-up visits. The key secondary efficacy endpoint was mean perioperative hemoglobin concentration of postoperative days 0, 2 and 4, assessing the non-inferiority of additional phosphate supplementation. We randomly consented 46 patients in each group (mean ± SD age 56 ± 17 years, 57 % female). Minimal phosphate concentration was 0.49 ± 0.21 mmol/L in the treatment group and 0.42 ± 0.17 mmol/L in the placebo group (p = 0.12, two-sided p-value). Average mean hemoglobin was 110 ± 16 g/L in the treatment and 113 ± 13 g/L in the placebo group (p = 0.023, one-sided p-value for non-inferiority). Hypophosphatemia occurred in 32 patients (70 %) of the treatment group and in 39 patients (85 %) of the placebo group (odds ratio 0.15, 95 % CI from 0.02 to 0.77, p = 0.014). Secondary outcomes, such as rescue medication use, core muscle strength and MOCA test scores, did not differ between groups. Co-administration of oral phosphate supplementation to ferric carboxymaltose cannot prevent hypophosphatemia. However, hypophosphatemia occurs in fewer patients. Phosphate co-administration did not impede the treatment of iron deficiency anemia with ferric carboxymaltose. •Ferric carboxymaltose may induce fibroblast growth factor 23 mediated hypophosphatemia.•We evaluated the effect of oral phosphate supplementation on mitigating hypophosphatemia caused by ferric carboxymaltose.•Oral phosphate supplementation cannot prevent hypophosphatemia but, hypophosphatemia occurs in fewer patients.

Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsies. We included 30 CIAP-patients, 28 with diabetic distal symmetrical polyneuropathy (DSPN) and 31 healthy controls. We assessed standardised scales, tested for the metabolic syndrome, measured 1-deoxySLs in plasma, performed electroneurography and studied 17 sural nerve biopsies (10 CIAP; 7 DSPN). One third of the CIAP-patients had a metabolic syndrome, significantly less frequent than DSPN-patients (89%). Although the metabolic syndrome was not significantly more prevalent in CIAP compared to healthy controls, hypercholesterolemia did occur significantly more frequent. 1-deoxySLs were significantly and equally elevated in both patient groups compared to healthy controls. Mean basal lamina thickness of small endoneurial vessels and the number of CD68- or CD8-positive cells in biopsies of CIAP- and DSPN-patients did not differ significantly. However, the number of leucocyte-common-antigen positive cells was significantly increased in CIAP. A non-significant trend towards a higher occurrence of the metabolic syndrome in CIAP-patients compared to healthy controls was found. 1-deoxySLs were significantly increased in plasma of CIAP-patients. Microangiopathy and an inflammatory component were present in CIAP-biopsies.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.

Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 ( Clos ). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H 2 O 2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut–vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging. Saeedi Saravi and colleagues demonstrate an age-related increase in the gut microbial metabolite phenylacetic acid (PAA) in humans and mice, linked to Clostridium bacteria. In mice, they find that PAA triggers endothelial senescence, linking the microbiome to vascular aging.

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1 , 2 ), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3 – 8 ); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL–protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum–Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure. Griess et al. determine the lipid signatures of pancreatic islets in type 2 diabetes models. They define a lipid environment linking the endoplasmic reticulum–Golgi transport protein Tmed2 to the proinsulin processing enzyme Pcsk1 to ensure insulin production.

BACKGROUND. Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. METHODS. A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. RESULTS. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS7-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. CONCLUSION. We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems. TRIAL REGISTRATION. Not applicable. FUNDING. Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.