Metabolic diseases such as diabetes, steatohepatitis, and coronary artery disease result from the delivery of nutrients that exceed a tissue’s energetic needs or storage capacity. The excess nutrients give rise to deleterious lipid species that impair cellular function. Summers and colleagues found that ceramides, a class of sphingolipids, alter the metabolism of liver and adipose tissue in a way that gives rise to cardiometabolic disease. They also discovered that removing a single double bond from ceramides is sufficient to restore metabolic homeostasis in diseased rodents. Lastly, they discovered that circulating ceramides were potent biomarkers of coronary artery disease. These results have inspired drug discovery efforts to lower ceramides and improve cardiometabolic health.
Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Chaurasia B, Tippetts TS, Mayoral Monibas R, Liu J, Li Y, Wang L, Wilkerson JL, Sweeney CR, Pereira RF, Sumida DH, Maschek JA, Cox JE, Kaddai V, Lancaster GI, Siddique MM, Poss A, Pearson M, Satapati S, Zhou H, McLaren DG, Previs SF, Chen Y, Qian Y, Petrov A, Wu M, Shen X, Yao J, Nunes CN, Howard AD, Wang L, Erion MD, Rutter J, Holland WL, Kelley DE, Summers SA. Science. 2019 Jul;365(6451):386.
Metabolic messengers: Ceramides. Summers SA, Chaurasia B, Holland WL Nature Metabolism. 2019 Oct:1051
Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease. Poss AM, Maschek JA, Cox JE, Hauner BJ, Hopkins PN, Hunt SC, Holland WL, Summers SA, Playdon MC. J Clin Invest. 2019 Nov. pii: 131838.