Neutral sphingomyelinase-2 and cardiometabolic diseases

Abstract

Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin resistance, pancreatic ß-cell dysfunction, type 2 diabetes, atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin, catalyzed by different sphingomyelinases, including neutral sphingomyelinase 2 (nSMase2), whose dysregulation appears to underlie many of the inflammation-related pathologies. In this review, we discuss the current knowledge on the biochemistry of nSMase2 and ceramide production and its regulation by inflammatory cytokines, with particular reference to cardiometabolic diseases. nSMase2 contribution to pathogenic processes appears to involve cyclical feed-forward interaction with proinflammatory cytokines, such as TNF-α and IL-1ß, which activate nSMase2 and the production of ceramides, that in turn triggers the synthesis and release of inflammatory cytokines. We elaborate these pathogenic interactions at the molecular level and discuss the potential therapeutic benefits of inhibiting nSMase2 against inflammation-driven cardiometabolic diseases.

Keywords: cardiometabolic diseases; ceramide; nSMase2; sphingolipid.

FIGURE 1

Signaling cascade of ceramides from their production to the pathogenesis of metabolic disorders. Ceramides can be synthesized de novo from palmitoyl‐CoA, from sphingomyelin through SMases, from sphingosine via ceramide synthase, and from ceramide‐1‐phosphate (C‐1‐P) through its phosphatase. Accumulation of ceramides causes oxidative stress and the activation of different protein kinases, which leads to mitochondrial dysfunction, apoptosis, insulin resistance, and inflammation. These processes contribute to pathogenesis of metabolic diseases. CVD: cardiovascular diseases; Ins Res: insulin resistance; NAFLD: nonalcoholic fatty liver disease; T2D: type 2 diabetes

FIGURE 2

Schematic representation of nSMase2 localization and regulation. nSMase2 can translocate from the Golgi apparatus to the plasma membrane, and this process is influenced by various factors. The enzymatic activity of nSMase2 can be modulated by oxidative stress, inflammatory cytokines, glutathione, chemotherapeutic agents (daunorubicin), and the pharmacological inhibitor GW4869. GSH: glutathione; PKCδ: protein kinase C isoform‐δ; PS: phosphatidylserine; ROS: reactive oxygen specie; SM: sphingomyelin; TNF‐α: tumor necrosis factor‐α. Created with BioRender.com

FIGURE 3

Pathways of insulin signaling inhibition by nSMase2 activation and ceramides. Ceramides produced from sphingomyelin by nSMase2 can activate PKCζ, PP2A, and PKR/JNK, all of which can impair insulin signaling by blocking the translocation of glucose transporter (GLUT)‐4 to plasma membrane. Accumulation of ceramides increases proinflammatory cytokine levels, which can also lead to insulin resistance. In addition, secreted TNF‐α and IL‐1β can in turn activate nSMase2, accelerating ceramide production. INSR: insulin receptor; IRS‐1/2: insulin receptor substrates 1 and 2; Pal‐CoA: palmitoyl‐CoA; SM: sphingomyelin; SMS: sphingomyelin synthase; TNFR: TNF‐α receptor. Created with BioRender.com

FIGURE 4

Proposed role of nSMase2 and ceramides in the pathogenesis of different metabolic diseases. The chronic low‐grade inflammation in individuals with obesity drives the production of proinflammatory cytokines such as TNF‐α and IL‐1β, which can lead to the upregulation of nSMase2 expression and activity. This, in turn, increases the production of ceramides leading to mitochondrial dysfunction, production of reactive oxygen species (ROS) and insulin resistance. Accumulation of ceramides in different organs seems to be responsible for the onset of different metabolic diseases. Created with BioRender.com