You aren't IMMUNE to the ceramides that accumulate in cardiometabolic disease

Abstract

Obesity leads to persistent increases in immune responses that contribute to cardiometabolic pathologies such as diabetes and cardiovascular disease. Pro-inflammatory macrophages infiltrate the expanding fat mass, which leads to increased production of cytokines such as tumor necrosis factor-alpha. Moreover, saturated fatty acids enhance signaling through the toll-like receptors involved in innate immunity. Herein we discuss the evidence that ceramides-which are intermediates in the biosynthetic pathway that produces sphingolipids-are essential intermediates that link these inflammatory signals to impaired tissue function. We discuss the mechanisms linking these immune insults to ceramide production and review the numerous ceramide actions that alter cellular metabolism, induce oxidative stress, and stimulate apoptosis. Lastly, we evaluate the correlation of ceramides in humans with inflammation-linked cardiometabolic disease and discuss preclinical studies which suggest that ceramide-lowering interventions may be an effective strategy to treat or prevent such maladies.

Keywords: Cytokine; Diabetes; Heart disease; Inflammation; Sphingolipids; Steatosis.

Figure 1.. Synthesis of ceramides.

Ceramides are formed from 3 pathways. A ubiquitous de novo biosynthetic pathway (yellow) is initiated by the condensation of fatty acid and amino acid. A salvage pathway (beige) allows liberated sphingosines or sphinganines to be used to re-generate ceramides. Sphingomyelin hydrolysis (blue) rapidly generates ceramides in response to the activation of sphingomyelinase enzymes. Created with BioRender.Com.

Figure 2.. Regulation of Ceramide Production by Inflammatory Agonists.

Receptors involved in innate immunity such as TLR4, as well as the inflammatory cytokines such as TNFα and IL-1β that they produce, induce enzymes required for de novo ceramide synthesis. The IKK/NFκB pathway is one pathway that upregulates the genes that encode these biosynthetic factors. Ceramides can also be acutely generated from sphingomyelin by TNFa receptor (TNFa-R) activated sphingomyelinase (SMase). They can be degraded by adiponectin receptors (Adipo-R), which are ceramidases. Created with BioRender.Com.

Figure 3:. Schematic depicting the array of ceramide actions that have been seen in cells.

Ceramides alter fuel choice to increase reliance on fatty acids and elicit other cellular responses that reduce the fatty acid burden on cellular membranes. For example, ceramides decrease reliance on glucose and amino acids for energy, in part by inhibiting Akt. Second, ceramides protect cellular membranes by enhancing production of sphingomyelin (SM)—a key component of detergent resistant lipid rafts—and inserting fatty acid translocases (CD36) into the membrane. Third, ceramides enhance storage of triglycerides by inhibiting HSL and inducing SREBP. Fourth, ceramides decrease mitochondrial efficiency to enable the release of electrons produced from excessive fatty acid oxidation in the form of ROS. Ultimately, when ceramides rise to even higher levels, they induce apoptosis and perhaps fibrosis, as the organism seems to rid itself of a compromised cell. Green text denotes cellular functions that are increased, while red text denotes functions that are decreased. Figure was generated with the help of Servier Medical Art. Created with BioRender.Com