👤 Silke Hornemann

Cholesterol efflux capacity (CEC) of HDL (high-density lipoprotein) is inversely associated with incident cardiovascular events, independent of HDL cholesterol. Obesity is characterized by low HDL cholesterol and impaired HDL function, such as CEC. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), broadly leads to improved cardiovascular outcomes, but impacts on risk factors differ by procedure, with greater improvements in weight loss, blood pressure, and glycemic control after RYGB, but greater improvements in HDL cholesterol and CEC levels after SG. This study sought to determine effects of RYGB and SG on HDL protein and lipid cargo and investigate associations with CEC changes. We prospectively studied nondiabetic, premenopausal Hispanic women with severe obesity not using lipid medications undergoing RYGB (n=31) or SG (n=36). Anthropometric measurements and blood sampling were obtained before and at 6 and 12 months after surgery. HDL was isolated from plasma, and quantitative proteomic and lipidomic assessments were performed with LC-MS/MS (liquid chromatography with tandem mass spectrometry). CEC was assessed ex vivo using apoB-depleted serum. Participants experienced similar, significant weight loss over 12 months following bariatric surgery (38.0±10.4 kg) regardless of the procedure. Relative quantities of 47 proteins (34 increased, 13 decreased) and 150 lipids (71 increased, 79 decreased) carried on HDL were significantly altered following either surgical procedure. Proteins with similar aggregate response patterns were clustered into 15 groups (5 increased, 5 decreased, 5 minimal change) and lipids with similar aggregate responses into 25 groups (7 increased, 11 decreased, 7 minimal change). Network mediation analyses suggested that changes in 4 protein and 2 lipid clusters mediated changes in ABCA1 (ATP-binding cassette transporter A1) CEC and that 1 lipid cluster mediated changes in non-ABCA1 CEC. The protein and lipid clusters that mediated changes in CEC were distinct between SG and RYGB. Bariatric surgery produces substantial changes in HDL lipid and protein cargo, and specific changes may mediate changes in HDL function in CEC. Further study of these mechanisms may lead to improved interventions to reduce cardiovascular risk in patients with obesity. Show less

Sphingolipids (SL) are crucial components of cellular membranes and play pivotal roles in various biological processes, including cell growth, differentiation, apoptosis, and stress responses. All SL contain a sphingoid base (SPB) backbone which is the shared and class-defining element. SPBs are heterogeneous in length and structure. This review summarizes our current understanding on minor SPBs and the role of the serine palmitoyltransferase (SPT) in particular of its subunits SPTLC3 and SPTSSA/B in forming a spectrum of structurally and metabolically distinct SPBs. Some minor SPBs, such as 1-deoxysphingolipids (1-deoxySL) are neurotoxic and associated with neurological disorders such as hereditary sensory neuropathy type 1 (HSAN1) and diabetic neuropathy. Furthermore, the review discusses the pathological implications of atypical SPBs in cardiometabolic conditions such as obesity, type 2 diabetes or cardiomyopathy, where the induction of the SPTLC3 subunit alters the SPB profile and contributes to disease progression. Understanding these, often neglected aspects of the sphingolipid metabolism provides potential therapeutic targets for metabolic and neurodegenerative diseases, emphasizing the need for continued research in this area. Show less

Sphingolipids (SL) represent a structurally diverse class of lipids that are central to cellular physiology and neuronal development and function. Defects in the sphingolipid metabolism are typically associated with nervous system disorders. The C4-dihydroceramide desaturase (DEGS1) catalyzes the conversion of dihydroceramide to ceramide, the final step in the SL de-novo synthesis. Loss of function mutations in DEGS1 cause a hypomyelinating leukodystrophy, which is associated with increased plasma dihydrosphingolipids (dhSL) and with the formation of an atypical SPB 18:1(14Z);O2 metabolite. Here, we characterize two novel DEGS1 variants of unknown significance (VUS), provide a structural model with a predicted substrate binding site, and propose a regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3). Both VUS involve single amino acid substitutions near the C-terminus within conserved regions of the enzyme. Patient 1 (p.R311K variant) shows severe progressive tetraspasticity, intellectual disability, and epilepsy in combination with brain magnetic resonance imaging (MRI) findings, typical for DEGS1-related leukodystrophy. Patient 2 (p.G270E variant) presents with delayed psychomotor development, oculomotor apraxia, and a normal brain MRI. Plasma from the p.R311K carrier showed a significantly elevated dhSL species and the presence of SPB 18:1(14Z);O2, while the plasma SL profile for the p.G270E variant was not altered. This suggests the p.R331K variant is pathogenic, while the p.G270E appears benign. As an increase in dihydroSL species is also seen in other pathological disorders of the SL metabolism, the SPB 18:1(14Z);O2 seems to be a more specific biomarker to discriminate between pathogenic and benign DEGS1 variants. Show less

Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort ( Show less

The incidence of obesity and metabolic syndrome (MetS) has rapidly increased worldwide. Roux-en-Y gastric bypass (RYGB) achieves long-term weight loss and improves MetS-associated comorbidities. Using a mouse model with a humanized lipoprotein metabolism, we elucidated whether improvements in lipid and glucose metabolism after RYGB surgery are body weight loss-dependent or not. Male ApoE*3Leiden.CETP (ApoE3L.CETP) mice fed Western type diet for 6 weeks underwent RYGB or Sham surgery. Sham groups were either fed ad libitum or were body weight-matched (BWm) to the RYGB mice to discriminate surgical effects from body weight loss-associated effects. Before and after surgery, plasma was collected to assess the metabolic profile, and glucose tolerance and insulin sensitivity were tested. Twenty days after surgery, mice were sacrificed, and liver was collected to assess metabolic, histological and global gene expression changes after surgery. RYGB induced a marked reduction in body weight, which was also achieved by severe food restriction in BWm mice, and total fat mass compared to Sham ad libitum mice (Sham AL). Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and ceramide were strongly reduced 20 days after surgery in RYGB compared to BWm mice. Glucose tolerance and insulin sensitivity improved 13 days after surgery similarly in RYGB and BWm mice. Liver histology confirmed lipid reduction in RYGB and BWm mice while the transcriptomics data indicated altered genes expression in lipid metabolism. RYGB surgery improves glucose metabolism and greatly ameliorates lipid metabolism in part in a body weight-dependent manner. Given that ApoE3L.CETP mice were extensively studied to describe the MetS, and given that RYGB improved ceramide after surgery, our data confirmed the usefulness of ApoE3L.CETP mice after RYGB in deciphering the metabolic improvements to treat the MetS. Show less

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases. Show less