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Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology.

ABSTRACT: Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk.

SUBMITTER: Wittenbecher C

PROVIDER: S-EPMC8854598 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology.

Wittenbecher C C Cuadrat R R Johnston L L Eichelmann F F Jäger S S Kuxhaus O O Prada M M Del Greco M F F Hicks A A AA Hoffman P P Krumsiek J J Hu F B FB Schulze M B MB

Nature communications 20220217 1

Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides ...[more]

PMID: 35177612

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Project description:Background – Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder that is characterized by the presence of left ventricular hypertrophy with histological evidence of myocyte disarray and fibrosis. Pathologic DNA variants in sarcomeric genes are seen in 50–60% of families, but the mechanistic origins of hypertrophy and disarray remain poorly understood. More molecular insights could contribute to a better understanding of these origins and improve therapeutic strategies for HCM. Methods – To identify gene expression patterns relevant to HCM pathology, we quantified intercellular heterogeneity in cardiomyocyte gene expression by performing single-cell RNA sequencing (scRNA-seq) on myectomy tissue from HCM patients. Results – Septal myectomy samples provide a unique opportunity to access diseased human heart tissue for scRNA-seq. We analysed gene expression of individual cardiomyocytes for three HCM patients, who each showed a similar presence of cardiomyocyte subpopulations. This similarity indicated these subpopulations emerge from biological processes, and not from experimental variability. Moreover, our data revealed functional links between genes important to HCM. A subpopulation characterized by elevated titin (TTN) expression showed increased expression of genes involved in muscle contraction and development. A subpopulation of Natriuretic Peptide A (NPPA)-enriched cells showed elevated expression of Natriuretic Peptide B (NPPB). Further analysis of gene co-expression revealed five groups of genes with tightly correlated expression (regulons), one consisting of mostly sarcomeric genes and another containing some well-known stress markers. These correlations were confirmed in 97 additional HCM myectomy samples and allowed us to de novo identify transcription factors related to sarcomeric gene expression and stress. Finally, using forward scatter, we charted functional implications of regulon expression and showed a link between the stress-marker regulon and cell size. Histology samples independently confirmed that regulon member skeletal alpha actin (ACTA1) correlates with cell size. Conclusion – We have shown that single-cell sequencing on myectomy samples from HCM patients identified new functional links between genes, transcription factors, and a functional link between genes and cell size. This highlights the relevance of cardiomyocyte heterogeneity, and additionally provides a wealth of novel insights into molecular events at the base of HCM, which potentially contribute to understanding disease progression.

Dataset Information

Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology.

Publications

Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology.

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