Contribution of specific ceramides to obesity-associated metabolic diseases

Abstract

Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.

Keywords: Atherosclerosis; Ceramide acyl chain length; Diabetes; High-fat diet; Insulin resistance; Lipid signaling; Lipotoxicity; Metabolic disease treatment; Obesity; Sphingolipids.

Fig. 1

Ceramide metabolism in mammals. Schematic representation of the ceramide metabolic pathway highlighting critical enzymes involved in ceramide turnover and their respective inhibitors. Six different ceramide synthases (CerS1-6) produce (dihydro)ceramides of varying acyl chain lengths by catalyzing the N-acylation of sphinganine (derived from the condensation of serine and palmitoyl-CoA; de novo pathway; highlighted in orange) or sphingosine (derived from sphingolipid breakdown; salvage pathway; highlighted in green) with a fatty acyl chain of defined length within the range C₁₄–C₂₆. Ceramides can also be derived from the hydrolysis of sphingomyelin (highlighted in purple). Ceramides serve as substrates for more complex sphingolipid species such as glucosylceramides and galactosylceramides, which can be further modified. Ceramides can also be converted to acylceramide species bearing an additional acyl chain at the 1-hydroxy position. ACSL5 Acyl-CoA synthetase long-chain family member 5, CDase ceramidase, CerS ceramide synthase, CGT ceramide UDP-galactosyltransferase, DEGS dihydroceramide desaturase, DGAT2 diacylglycerol O-acyltransferase 2, GALC galactosylceramidase, GCase glucocerebrosidase, GCS glucosylceramide synthase, KDSR 3-ketodihydrosphingosine reductase, ORMDL orosomucoid-like protein, R Fatty acyl chain moiety, SGPL1 sphingoine-1-phosphate lyase 1, SGPP1 sphingosine-1-phosphate phosphatase 1, SK sphingosine kinase, SMase sphingomyelinase, SMS sphingomyelin synthase, SPT serine palmitoyltransferase, UGCG UDP-glucose ceramide glucosyltransferase, UGT8 UDP glycosyltransferase

Fig.2

Cellular and molecular mechanisms by which ceramides affect metabolic regulation. Excessive influx of free fatty acid (FFA) mediated by the fatty acid transporter CD36 drives the production of ceramides, which exert multifaceted effects to modulate cellular metabolic homeostasis. Ceramide-dependent effects are shown by black arrows, including regulatory proteins through which they act. The consequences of ceramide accumulation are highlighted in red, and the underlying mechanisms are highlighted in blue. Purple arrows depict conversion of lipids, and dashed lines indicate transport. AKT protein kinase B, BAX Bcl-2-associated X protein, CD1d cluster of differentiation 1d, CD36 cluster of differentiation 36 (fatty acid transporter), CerS ceramide synthase, DES dihydroceramide desaturase, eNOS endothelial NO synthase, ER endoplasmic reticulum, FA-CoA fatty acyl-coenzyme A, FFA free fatty acid, GalCer galactosylceramide, GLUT4 glucose transporter 4, HSL hormone-sensitive lipase, iNKT invariant natural killer T cell, IR insulin receptor, JNK c-Jun-N-terminal kinase, KDSR 3-ketodihydrosphingosine reductase, MFF mitochondrial fission factor, MOMP mitochondrial outer membrane permeabilization, NLRP3 NLR family pyrin domain-containing 3, NO nitric oxide, PC phosphatidylcholine, PERK protein kinase RNA-like ER kinase, PKCζ protein kinase C zeta, PKR protein kinase R, PM plasma membrane, PP2A protein phosphatase 2A, SPT serine palmitoyltransferase, SREBP1 sterol regulatory element-binding protein 1, STARD7 StAR-related lipid transfer protein 7, TAG triacylglycerol, VDAC2 voltage-dependent anion channel 2

Fig. 3

Factors potentially contributing to ceramide accumulation in obesity. In conjunction with the increased availability of precursor fatty acids for ceramide production, several cell-extrinsic and -intrinsic factors have been linked to the control of ceramide turnover rate and may contribute to ceramide accumulation when deregulated in obesity. AMPK AMP-activated protein kinase, Asah N-acylsphingosine aminohydrolase (acid CDase), Acer2 alkaline ceramidase 2, CerS ceramide synthase, FFA free fatty acids, FGF21 fibroblast growth factor 21, FXR farnesoid X receptor, HIF2α hypoxia-induced factor 2α, MYC transcription factor MYC, Neu3 neuraminidase 3, Smpd3 sphingomyelin phosphodiesterase 3 (neutral SMase2), Sptlc serine palmitoyltransferase long-chain base subunit

Fig. 4

Tissue-specific effects of ceramide accumulation and the related health consequences in obesity. Most conclusive observations have been demonstrated in rodent models of obesity or dyslipidemia. Although ceramides have been associated with obesity-related metabolic dysfunction and disease development in all tissues shown, the exact ceramide molecular species involved in these processes often remain undefined. If there is evidence of the ceramide species promoting tissue-specific lipotoxicity, this is indicated accordingly. Red arrows indicate inhibitory effects, and green arrows indicate stimulatory effects. Cer ceramide, CerS ceramide synthase, ER endoplasmic reticulum, FFA free fatty acid, HGP hepatic glucose production, LDL low density lipoprotein, NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis, NO nitric oxide, PVH paraventricular hypothalamus, VMH ventromedial hypothalamus