Characterizing a Common CERS2 Polymorphism in a Mouse Model of Metabolic Disease and in Subjects from the Utah CAD Study

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 8; pp. e3098 - e3109
• Main Authors: Nicholson, Rebekah J, Poss, Annelise M, Maschek, J Alan, Cox, James E, Hopkins, Paul N, Hunt, Steven C, Playdon, Mary C, Holland, William L, Summers, Scott A
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2021
• Subjects: Adult; Alleles; Amino acid substitution; Analysis; Animals; Cardiovascular disease; Cardiovascular diseases; Ceramide; Clinical s; Clustered Regularly Interspaced Short Palindromic Repeats; Coronary artery disease; Coronary heart disease; Coronary vessels; CRISPR; Dextrose; Disease Models, Animal; Enzymatic activity; Enzymes; Fatty liver; Female; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Glucose; Glucose tolerance; Heart diseases; Homeostasis; Humans; Liver; Male; Mass spectrometry; Mass spectroscopy; Medical research; Medicine, Experimental; Membrane lipids; Membrane Proteins - genetics; Metabolic disorders; Mice; Middle Aged; Mutation; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Sphingolipids; Sphingosine N-Acyltransferase - genetics; Steatosis; Tumor Suppressor Proteins - genetics; Utah; Vein & artery diseases; Utah; United States > US; ceramide synthase 2; GWAS; sphingolipids; diabetes; lipid metabolism; hepatic steatosis
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgab155

Abstract Context Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP; rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. Objective The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. Design We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles. Results In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count. Conclusions The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.