Metabolic Messengers: ceramides

Abstract

Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.

The accumulation of ectopic lipid metabolites in tissues not suited for fat storage drives the cellular dysfunction that underlies diabetes and heart disease. Of the numerous types of lipids that accumulate, sphingolipids such as ceramides are amongst the most deleterious, because they modulate signalling and metabolic pathways driving insulin resistance, triglyceride production, apoptosis and fibrosis. Inhibition of ceramide biosynthesis in rodents ameliorates insulin resistance^1,2, hepatic steatosis^1–7, hypertriglyceridemia^1,2,8, atherosclerosis^9–14, type 2 diabetes¹ and heart failure^15,16. Moreover, ceramide degradation is a primary means by which adiponectin receptors, which are ligand-activated ceramidases, exert their anti-diabetic, cardioprotective and insulin-sensitizing actions^17,18. Owing to a strong association between serum ceramides and both insulin resistance and major adverse cardiac events, the Mayo Clinic is now marketing tests to measure circulating ceramides as markers of cardiovascular mortality^19,20. Here, we review the history of research on these important molecules and discuss the evolutionary pressures that may have endowed them with such important roles as signals of lipid overload.

Discovery of ceramides as signalling molecules

Within the past 30 years, researchers have elucidated the molecular composition of sphingolipids and the biochemical pathways that control their production in great molecular detail. Owing largely to the work of Alfred Merrill, an exceptional analytical chemist and mass spectroscopist, great progress has been made in discerning the sphingolipidome. The LIPID MAPS Lipidomics Gateway (http://www.lipidmaps.org/) now lists 4,000 distinct chemical entities within this lipid class. Researchers have also cloned and characterized most enzymes involved in sphingolipid synthesis and degradation²¹.

Ceramides, which are the precursors of most sphingolipids, are produced through a four-step biosynthetic cascade initiated by the condensation of palmitoyl-CoA and serine²¹. This first reaction, catalysed by serine palmitoyltransferase (SPT), generates ketosphinganine, which is rapidly converted by 3-ketosphinganine reductase into sphinganine. This sphingoid scaffold subsequently acquires additional fatty acids, thus producing dihydroceramides. The Futerman laboratory has characterized the (dihydro)ceramide synthase (CERS) enzymes that add this second acyl chain, and has rigorously examined the substrate specificity and tissue distribution of the six CERS isoforms²². Dihydroceramide desaturase isoforms 1 and 2 (DES1 and DES2) insert an essential double bond into the sphingoid base of dihydroceramides, thus producing ceramides. Various head groups can be added to ceramides to produce the predominant complex sphingolipids, including sphingomyelin and gangliosides. Ceramides are the first point of substantial sphingolipid accumulation.

In the late 1980s and early 1990s, pioneering studies in the Hannun, Obeid and Kolesnick laboratories revealed that stress stimuli such as tumour necrosis factor activate sphingomyelinases, thereby acutely liberating ceramides. The subsequent paradigm-shifting work of these researchers established that ceramides function as intracellular messengers^23–25. Initially, much of the effort was devoted to understanding the ability of ceramides to induce apoptosis²⁵. Building on these discoveries, the Unger laboratory found that ceramides produced by de novo synthesis are obligate intermediates linking saturated fatty acids to pancreatic beta-cell apoptosis, thus suggesting for the first time that ceramides play a key role in the beta-cell failure that underlies diabetes^26,27.

In the late 1990s, studies by our group and others demonstrated that ceramides also inhibit insulin-stimulated glucose uptake^28,29. In particular, ceramide analogues block activation of Akt (PKB), an insulin-responsive serine/threonine kinase essential for GLUT4 glucose-transporter translocation, cell survival (that is, anti-apoptosis) and the synthesis of glycogen, fatty acids and protein^28,30. These studies, which suggested roles for ceramides in the development of insulin resistance, laid the foundation for the topic discussed here: ceramides as metabolic messengers (Fig. 1).

Fig. 1 |. Discovery of ceramides as metabolic messengers.

Nearly 100 years passed between the discovery of sphingolipids (1884) and the determination that sphingolipids such as ceramides have biological activities as intracellular messengers that alter cell survival and metabolism (1990s). In the mid- to late 2000s, a series of studies using pharmacological reagents (for example, myriocin) or genetically engineered mice revealed that blocking ceramide synthesis ameliorates atherosclerosis, diabetes and heart disease. Subsequently, adiponectin receptors were identified as ceramides, and the fields of research on these two metabolic messengers converged (2011–2017). As lipidomic technologies improved, large-scale lipidomic profiling studies became possible, revealing tight associations between serum and tissue ceramides and cardiometabolic disease (2014–2019). Finally, research in mice has revealed that making subtle modifications to the ceramide molecules (for example, by altering their acylation patterns or the desaturation status of the sphingoid backbone) is sufficient to ameliorate cardiometabolic disease, thus revealing new therapeutic strategies for combating these disorders (2014–2019).

Theory: an evolutionarily conserved role of ceramides as signals of lipid overload

Free fatty acids (FFA) are energy-dense molecules with amphipathic, detergent-like properties. Evolutionary pressures have equipped cells with means to rapidly incorporate FFA into macromolecules, thus ensuring that their intracellular concentrations remain very low. Immediately after entering cells, FFA couple to CoA, which prepares them for subsequent enzymatic modification. When energy needs are high, the resultant acyl-CoAs couple to carnitine, which allows them to be shuttled into mitochondria for beta-oxidation. When energy needs are low, these acyl-CoAs couple to glycerol and produce triglycerides—the major fuel store in the body—and the other glycerophospholipids that make lipid bilayers. When a cell’s energy needs are met and its triglyceride stores are saturated, acyl-CoAs enter the ceramide-biosynthesis pathway described above. Incorporation of FFA into these complex structures (for example, acyl-CoAs, glycerolipids and sphingolipids) prevents them from concentrating in bilayers; otherwise, they would aberrantly disrupt the bilayer structure.

We speculate that the sphingolipids, and particularly the ceramides, that accumulate under conditions of nutritional overload initiate actions that help cells handle the excessive incoming fatty acids (Fig. 2, right). The following activities are consistent with this role:

1. Although FFA can diffuse through cellular membranes, their uptake can be facilitated by translocases such as CD36, which also accelerate their esterification^31,32. Ceramides promote the translocation of CD36 to plasma membranes^2,17, thus supporting the safe transport of FFA across membranes and enhancing their rapid conversion into acyl-CoAs.

2. Ceramides induce and/or activate genes (for example, SREBP genes) that promote the incorporation of FFA into triglycerides and facilitate their storage in lipid droplets^2,33.

3. Ceramides inhibit the uptake of glucose^28,29 and amino acids^34–36, thus leading to the preferential utilization of fatty acids for energy. This conserved attribute of sphingolipids is present in single-cell organisms, such as yeast^36–39, as well as being an underlying cause of mammalian insulin resistance¹.

4. Ceramides decrease mitochondrial efficiency, inhibiting oxygen consumption through the complexes of the electron-transport chain and decreasing mitochondrial membrane potential, thereby leading to a decrease in the amount of ATP produced by a given fatty acid molecule^3,40–42. Lower mitochondrial efficiency ultimately allows the cell to burn more fatty acids, because it decreases the effect of reducing equivalents produced from fat metabolism on the electrochemical gradient across the inner mitochondrial membrane.

5. Ceramides slow lipolysis by blocking activation of hormone-sensitive lipase (HSL)².

Fig. 2 |. Ceramides as signals of lipid excess.

Left, simplified schematic of the ceramide-biosynthesis pathway, highlighting enzymes discussed in this review. Pharmacological inhibition or genetic depletion of SPT, CERS1, CERS6 and DES1 lowers ceramides and ameliorates insulin resistance and cardiometabolic disorders. Moreover, transgenic overexpression of ASAH1, ADIPOR1 or ADIPOR2 produces the same beneficial effects. Right, simplified schematic depicting the central hypothesis that ceramides are gauges of FFA excess. The mechanisms that ceramides invoke are as follows: (1) redistribution of CD36 toward the plasma membrane, thus facilitating the safe uptake of FFA and enhancing the conversion of fatty acids into acyl-CoA; (2) induction of Srebf1, thus stimulating the synthesis of cholesterol, a partner of ceramide and sphingomyelin in lipid rafts, and inducing genes that facilitate the conversion of FFA into inert triglycerides; (3) inhibition of Akt (PKB), which slows glucose utilization in adipose tissue and muscle, thus facilitating the usage of lipids for energy, while inhibiting hepatic gluconeogenesis; (4) inhibition of HSL, which prevents liberation of additional FFA from lipid droplest; (5) inhibition of mitochondrial complexes, thus calibrating the metabolic efficiency in situations with energy surplus; (6) repression of lipase expression by ceramide synthases. KDSR, 3-ketodihydrosphingosine reductase; ASAH1, acid ceramidase; MFF, mitochondrial fission factor.

Each of these mechanisms lowers levels of FFA, by promoting either their storage as triglycerides or their utilization for energy. Most of these actions have been shown by using both short-chain ceramide analogues (for example, C2 ceramide) and by specific experimental manipulations to modulate the endogenous ceramide pool. The exceptions are the activation of HSL and the inhibition of mammalian amino acid transporters, which, to our knowledge, have been shown only by using C2 ceramide.

Many of these actions result from ceramide activation of two downstream effectors: protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A). PKCζ mediates ceramide effects on Akt (PKB)^43–45, which regulates glucose uptake, as well as CD36 (ref.⁴⁶) and SREBP^7,47. PP2A regulates Akt (PKB)^48–50 and HSL⁵¹. Of note, Akt (PKB) is modulated by both PKCζ and PP2A through distinct and separable mechanisms^48,49. Inhibition of Akt (PKB) is likely to inhibit synthesis of new fatty acids, although this has never been shown experimentally.

The mechanisms by which ceramides inhibit mitochondrial efficiency have, until recently, been elusive. Large, extended mitochondria produced by fusion display enhanced mitochondrial efficiency; they are often elevated in cells with high respiratory activity⁵². On the opposite end of the spectrum, mitochondria can be fragmented through fission, which renders them less efficient and more susceptible to mitophagy⁵². Mitochondrial C16 ceramides have been found to promote mitochondrial fragmentation by interacting with mitochondrial fission factor⁵³. Remarkably, this mechanism involving ceramide and mitochondrial fission factor fully accounts for the increased mitochondrial fragmentation that occurs in mice fed an obesogenic diet⁵³. These results are consistent with prior findings by Bikman and colleagues⁵⁴, who have similarly concluded that fission is requisite for the impairment in oxygen consumption caused by short-chain ceramide analogues in vitro. Ceramides have also been proposed to alter mitochondrial membrane potential by forming channels in mitochondrial membranes.

Ceramides can also be converted to sphingomyelins, which are binding partners of sterols such as cholesterol. Sphingomyelin and cholesterol are components of caveolae, which are particularly abundant in adipocytes and serve as scaffolds that support fatty acid diffusion and uptake^55–57. Thus, sphingomyelins may also have a role in supporting the safe passage of detergent-like fatty acids across cellular membranes.

Some of the enzymes in the biosynthetic pathway serve dual functions beyond their role as enzymes that produce ceramides. For example, the Drosophila ceramide synthase (Schlank) and its mammalian isoform CERS2 have been shown to respond to fatty acids by translocating to the nucleus, where they repress transcription of lipases^58,59. This dual action of the enzymes that produce ceramides further prevents liberation of FFA from the lipid droplet, thus reinforcing the evolutionarily conserved role of the sphingolipid pathway as a means of protecting cells in situations of lipid surplus.

Collectively, these sphingolipid actions promote the utilization and storage of fatty acids (Fig. 2). Such cellular capabilities would be beneficial in instances of lipid surplus. We further predict that the well-known effects of ceramide on apoptosis^60–62 and fibrosis^63,64 may have evolved as an extension of this response, helping organisms rid themselves of compromised cells when FFA levels are particularly high. Such protective mechanisms would limit the damage resulting from the spilling of cytosolic components after aberrant FFA-driven membrane lysis.

Inhibition of ceramide biosynthesis ameliorates cardiometabolic diseases in rodents

Although the ceramide actions described above protect cells and/or organisms in times of acute nutritional overload, they are deleterious in the context of obesity. In particular, these ceramide actions explain the ‘selective’ insulin resistance⁶⁵ that characterizes the pre-diabetic condition. This state, which is exemplified by defective insulin action towards glucose but enhanced insulin-stimulated triglyceride production, increases the risk of diabetes, atherosclerosis, hypertension and heart failure. Indeed, ceramide-reduction interventions reverse selective insulin resistance⁵¹ and prevent the development of future cardiometabolic disorders^1,14,15. A summary of tissue-specific actions of ceramides in cardiometabolic disease is provided in Fig. 3.

Fig. 3 |. Target tissues and metabolic activities of ceramides.

Ceramides influence cardiometabolic disease in mice and humans. Most observations have been conclusively demonstrated in rodents and are supported by strong correlational data from humans. The physiological effects of ceramide are therefore strongly preserved between the two organisms. Ceramide effects include induction of insulin resistance, impairment in vascular reactivity, enhancement of triglyceride synthesis, impairment in lipid oxidation, inhibition of insulin gene transcription and stimulation of apoptosis and fibrosis.

The first studies to convincingly demonstrate the therapeutic potential of ceramide-reduction interventions were conducted with myriocin, an irreversible and high-affinity inhibitor of SPT. The compound was first used in ApoE-knockout mice, in which it prevented or reversed atherosclerosis^9–14. Shortly thereafter, studies in various rodent models (mice, rats and hamsters) revealed that SPT inhibition prevents or reverses insulin resistance^{1,3,8,66–68}, hepatic steatosis^1,3–7, type 2 diabetes¹, hypertension⁶⁹ and/or cardiomyopathy^15,16. Deletion of essential SPT subunits from mouse tissues recapitulates many of these myriocin actions^7,15,70.

We have recently found that excising the Degs1 gene (encoding dihydroceramide desaturase-1 (DES1), the enzyme that inserts an important double bond in the ceramide backbone) from adult mice fully reverses the pre-diabetic condition². In this study, total sphingolipid levels were unchanged, but the proportion of ceramides lacking the double bond (that is, dihydrosphingolipids) greatly increased. This double bond was found to be essential for all the mechanisms described above. Excising Degs1 from the whole body, liver or adipose tissue resolved hepatic steatosis and insulin resistance in leptin-deficient and high-fat-diet-fed mice. In contrast, ablation of Degs1 from intestinal or myeloid cells had no effect. These studies reinforce the importance of ceramides as regulators of glucose homeostasis and identify a tractable therapeutic target for reversing the pre-diabetic condition. These findings suggest that the formation of ceramide platforms, which is dependent on the double bond, is essential for the signalling mechanisms described herein.

The nature of the acyl chain attached to the sphingoid backbone also influences the ability of ceramides to initiate the actions described above. Specifically, ceramides containing C16:0 or C18:0 side chains serve as nutritional signals, whereas those containing much longer side chains such as C24:0 or C24:1 do not. For example, ablation of the Cers6 gene, which encodes the enzyme that makes C16:0 ceramides and is upregulated in obesity, from the whole body, brown adipose tissue or the liver, is sufficient to resolve insulin resistance and hepatic steatosis⁴². Excision of Cers5, which encodes the enzyme that makes C16:0 ceramides, has protective actions in the heart⁵¹, and excision of Cers1, which encodes the dominant isoform in skeletal muscle and the enzyme that makes C18 ceramides, improves insulin sensitivity⁷¹. In comparison, haploinsufficiency for Cers2, which encodes the major synthase isoform in the liver that makes very long-chain ceramides (for example, C24:0 or C24:1 ceramides), induces compensatory increases in Cers6 and C16:0 ceramides, thereby worsening the metabolic dysfunction caused by high-fat diets^3,42.

These data are consistent with the idea that the long-chain ceramides (for example, C16 ceramides) are uniquely capable of initiating the signalling pathways that influence cellular metabolism. Kolesnick and colleagues have reported that C16:0 ceramides, but not forms with longer acyl chains (that is, very long-chain ceramides), self-associate in non-bilayer macrodomains termed ceramide-rich platforms⁷². The authors have identified these membrane microdomains as sites that initiate downstream signalling and disrupt membrane structure. These biophysical attributes may account for the ability of C16 ceramides to serve as signalling nodes that alter the metabolic program of lipid-laden cells.

Serum and tissue ceramide predict the severity of cardiometabolic disease

Advances in mass spectroscopy and lipidomics have enabled researchers to measure sphingolipids in large tissue biobanks, revealing strong relationships between serum and tissue ceramides and insulin resistance, diabetes and major adverse cardiac events. Because of these associations, the Mayo Clinic now offers diagnostic tests to measure circulating ceramides as indices of cardiovascular risk^19,20. Herein, we briefly summarize the larger studies.

Serum profiling studies have revealed particularly strong relationships between certain ceramide species and major adverse cardiac events, insulin resistance and diabetes. (1) In studies of patients with or without coronary artery disease, ceramides containing the C16:0, C18:0 and C24:1 acyl chains have been found to display independent predictive value for future fatality and/or major adverse cardiac events exceeding those of conventional risk measures, including LDL cholesterol^73–81. Most of these studies were performed by Zora Biosciences, profiling individuals in Europe and North America. The total number of individuals screened in these studies now exceeds 70,000 (R. Laaksonen, personal communication). (2) Numerous additional groups have reported associations between serum ceramides and insulin resistance. In particular, Lemaitre and colleagues have profiled several thousand Native Americans (that is, the Strong Family Heart Study) at high risk for diabetes^82–84. Several ceramide species, including C16:0 and C18:0 ceramides, correlated with hyperinsulinemia and the homeostatic model of insulin resistance (HOMA-IR) in this at-risk population. These studies are consistent with earlier, smaller studies evaluating relationships between serum ceramides and insulin resistance in both humans and non-human primates^85–90. (3) Wigger and colleagues have identified relationships between dihydroceramides and ceramides and the development of diabetes⁹¹. The dihydroceramides, which are much less abundant and serve as good readouts of changes in ceramide flux, have been found to predict diabetes development up to 9 years in advance of disease onset.

Within tissues, the largest profiling study to date was performed by Yki-Jarvinen and colleagues, who characterized 125 liver biopsies. These authors have determined that C16:0 and other ‘saturated’ ceramides correlate strongly with insulin resistance, independently of steatosis⁹². In a follow-up study, these authors have found that overfeeding saturated fat leads to increases in harmful C16:0 ceramides in plasma and worsened insulin resistance⁹³.

The Goodpaster laboratory has found positive relationships between muscle ceramide levels and insulin resistance in several study populations^94–98. Similar findings have been reported by Mandarino and colleagues⁹⁹. Insulin-sensitizing treatments (such as metformin, pioglitazone, exercise and bariatric surgery) have all been found to decrease muscle ceramides^94–98.

Some recent studies have drawn attention to less abundant sphingolipids, such as deoxysphingolipids or other sphingolipids with a shorter sphingosine backbone. These are produced because of substrate promiscuity in serine palmitoyltransferase, which can occasionally use either alanine/glycine or myristoyl-CoA, instead of serine and palmitoyl-CoA, as substrates. Serum levels of these less abundant sphingolipids have also been found to be associated with cardiometabolic disease in humans and/or animal models^89,100–105.

Although the preponderance of profiling studies describes strong relationships between sphingolipids and indices of metabolic dysfunction, we acknowledge come controversy in the literature, because some earlier studies have reported that no such relationship exists between muscle or liver ceramides and insulin resistance^106,107. Some of these studies have involved infusion of a lipid emulsion comprising unsaturated fats^108–110, which induce insulin resistance via a ceramide-independent mechanism¹. For a longer discussion of this issue and the apparent discrepancy, we refer readers to a prior debate^111,112.

Regulation of ceramide synthesis and degradation

The concentration of precursor substrates (for example, palmitoyl-CoA and serine) is an important determinant of ceramide levels⁵⁰. Indeed, the aforementioned dietary studies have indicated that consumption of saturated fat increases levels of ceramides⁹³. Beyond that, a wealth of evidence has emerged demonstrating that rates of ceramide production and degradation can be further modified by other factors associated with obesity and cardiometabolic health and disease.

Adiponectin.

Adiponectin is an anti-diabetic and cardioprotective molecule released during fasting by small metabolically active adipocytes. During these periods, which are characterized by enhanced lipolysis, adiponectin migrates to other peripheral tissues, where it is insulin sensitizing and anti-apoptotic. Noting that adiponectin and ceramides had opposing effects, Holland and Scherer have hypothesized that the adipokine elicits its broad swath of actions by degrading ceramides. In particular, the authors have observed that adiponectin receptors (ADIPOR1 and ADIPOR2), as well as other members of the progesterone and adipoQ-receptor superfamily, show strong homology to intracellular ceramidases¹¹³. The authors subsequently determined that adiponectin promotes ceramide degradation and that deletion of an essential residue in the receptors’ ceramidase motif renders them ineffectual¹⁷. Moreover, they have found that overexpression of a ceramidase in adipose tissue or the liver is sufficient to mimic adiponectin actions⁴⁶. Granier and colleagues later solved the crystal structure of the receptor, revealing that it bears a strong resemblance to those of ceramidases¹⁸. Moreover, they have demonstrated that the purified receptor has ceramidase activity¹⁸. These data strongly suggest that adiponectin prevents ceramide accumulation when FFA are needed for energy production. Evidence for the clinical relevance of these findings is starting to emerge: adiponectin levels have been found to inversely correlate with serum and tissue ceramides in insulin resistant individuals^88,114.

β-adrenergic agonists.

We predicted that factors that liberate fatty acids from adipocytes, such as β-adrenergic agonists, would decrease ceramide levels, thus relieving their inhibition of HSL, releasing FFA and enhancing mitochondrial efficiency. Using a novel flux assay to monitor rates of ceramide production, we have found that β-adrenergic agonists rapidly and completely shut down ceramide biosynthesis in adipocytes².

Inflammatory agonists.

Inflammatory agonists (for example, Toll-like receptor-4 agonists (TLR4), tumour necrosis factor and interleukins) selectively increase levels of sphingolipids by upregulating enzymes in the de novo ceramide biosynthesis at pathway and by activating sphingomyelinases^{17,23–25,115}. Indeed, TLR4 signalling is required for palmitate induction of ceramides^17,116,117 and for lipid-induced insulin resistance^17,118–120. Of note, correlational studies have shown particularly tight relationships between plasma ceramides and insulin resistance in concert with levels of circulating inflammatory cytokines^115,121.

Farnesoid X receptors (FXR).

FXR are bile-acid-responsive nuclear receptors that modify bile acid, lipid and glucose metabolism. Gonzalez and colleagues have found that intestinal FXR is a strong inducer of non-alcoholic fatty liver disease, thus identifying it as an important link between changes in the microbiome and the disruption of liver metabolism^33,122–125. These authors have also found that FXR activation leads to the production of intestinal ceramides. Moreover, they have determined that these ceramides transmigrate to the liver, where they stimulate hepatic lipid deposition and gluconeogenesis. Thus, increased lipid-driven bile release in the gut activates a compensatory feedback loop that increases ceramides and signals the organism in times of lipid excess.

Determination of the precise means through which these factors influence ceramide levels may reveal exciting opportunities for therapeutic intervention to improve metabolic health.

Critical questions for future research

The data described above unequivocally identify ceramides as important nutrient signals that contribute to cardiometabolic disease. These transformative discoveries, although exciting, have led to several unresolved questions.

First, what is the importance of the double bond or the difference in acyl-chain lengths in conferring biological activity to ceramides? How do these small modifications influence the downstream signalling mechanisms that translate minor changes in ceramides into profound alterations in cellular metabolism and cardiometabolic health?

Second, what are the genetic determinants of ceramide accumulation in the population? Numerous single-nucleotide polymorphisms have been identified in ceramide-modifying enzymes. For example, Curran, Blangero and colleagues have identified an inactivating missense mutation in Degs1 that associates with increased dihydroceramides, and decreased ceramides, 2-h glucose, cholesterol esters and diabetes risk scores¹²⁶. However, many other rare variants have not been characterized. Will research reveal that these mutations have functional effects on sphingolipid profiles or disease risk? If so, can this information be used to develop personalized interventions to lower ceramides and improve health?

Third, will any of the enzymes that control ceramide production or degradation emerge as tractable therapeutic targets? Our research has focused on dihydroceramide desaturase-1, which expresses a favourable combination of druggability, biomarker availability and safety. Will small-molecule inhibitors of the enzyme show clinical utility? Or will other enzymes in the pathway (for example, one of the ceramide synthases or ceramidases) prove to be better targets for lowering ceramides to improve cardiometabolic health?

Fourth, can specific dietary or exercise regimens be developed to lower ceramides and improve patient health? What should we tell patients today with high ceramide scores?

Research addressing these important queries holds great promise for combating the metabolic disease epidemic.