Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation

Abstract

Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool.

Keywords: cardiovascular diseases; ceramides; diabetes; inflammation; lipotoxicity.

Figure 1

The three main pathways of ceramide biosynthesis. The de novo synthesis is a multistep pathway that starts with the condensation of serine with palmitoyl-CoA to form 3-ketosphinganine, which is the rate-limiting step and is catalyzed by serine palmitoyltransferase. In the second pathway, Cers are synthesized via the hydrolysis of the phosphocholine head groups of sphingomyelin by sphingomyelinases. In the salvage pathway, Cers are recycled from sphingosine re-acylation that is catalyzed by ceramide synthase.

Figure 2

Sphingolipid rheostat and the opposite effects of ceramides and S1P on cell fate.