J Lipid Atheroscler.  2020 Jan;9(1):50-65. 10.12997/jla.2020.9.1.50.

Ceramides: Nutrient Signals that Drive Hepatosteatosis

• Summers SA

• KMID: 2470800
• DOI: http://doi.org/10.12997/jla.2020.9.1.50

Abstract

Ceramides are minor components of the hepatic lipidome that have major effects on liver function. These products of lipid and protein metabolism accumulate when the energy needs of the hepatocyte have been met and its storage capacity is full, such that free fatty acids start to couple to the sphingoid backbone rather than the glycerol moiety that is the scaffold for glycerolipids (e.g., triglycerides) or the carnitine moiety that shunts them into mitochondria. As ceramides accrue, they initiate actions that protect cells from acute increases in detergent-like fatty acids; for example, they alter cellular substrate preference from glucose to lipids and they enhance triglyceride storage. When prolonged, these ceramide actions cause insulin resistance and hepatic steatosis, 2 of the underlying drivers of cardiometabolic diseases. Herein the author discusses the mechanisms linking ceramides to the development of insulin resistance, hepatosteatosis and resultant cardiometabolic disorders.

Keyword

Ceramides; Steatohepatitis; Insulin resistance; Non-alcoholic fatty liver disease; Diabetes

MeSH Terms

Carnitine
Ceramides*
Fatty Acids
Fatty Acids, Nonesterified
Fatty Liver
Glucose
Glycerol
Hepatocytes
Insulin Resistance
Liver
Metabolism
Mitochondria
Non-alcoholic Fatty Liver Disease
Triglycerides
Carnitine
Ceramides
Fatty Acids
Fatty Acids, Nonesterified
Glucose
Glycerol

Figure

• 

  Fig. 1 Schematic depicting the key reactions in the ceramide biosynthesis pathway. CoA, coenzyme A; SPT, serine palmitoyltransferase; KDHR, 3-ketodihydrosphingosine reductase; CERS, (dihydro)ceramide synthases (isoforms in parentheses); DES, dihydroceramide desaturase (isoforms in parentheses); GCS, glucosyceramide synthase; SMS, sphingomyelin synthase (isoforms in parentheses); CERK, ceramide kinase.

• 

  Fig. 2 Schematic depicting the pathways that incorporate fatty acids entering the cell. (A) When detergent-like fatty acid levels get too high, they emulsify cellular membranes. The lysis occurs over 3 stages: fatty acid penetration into the bilayer; their equilibration into both faces of the bilayer; and the transition of the bilayer into a micelle. (B) To prevent lysis, fatty acids entering the cell are quickly coupled to CoA and then incorporated into backbones to produce acylcarnitines, glycerolipids, and sphingolipids. Acylcarnitines are formed as fatty acids translocate into mitochondria. Glycerolipids that are produced make up the bulk of membrane bilayers and create the triglyceride stores that form the majority of the lipid droplet. Sphingolipids are signals of lipid excess that signal to upregulate the other 2 pathways under conditions of lipid excess. CoA, coenzyme A.

• 

  Fig. 3 Schematic depicting the means by which ceramides influence cellular metabolism. Mechanisms described in the text and depicted in greater detail in Fig. 4. SM, sphingomyelin; GLUT4, the insulin-responsive glucose transporter; Akt, the serine threonine kinase Akt/PKB; HSL, hormone-sensitive lipase; SREBP, sterol response element binding protein; MFF, mitochondrial fission factor; BAX, the pro-apoptotic BCL2 family member BAX; FFA, free fatty acid. Green denotes a process that is increased and red denotes decreased.

• 

  Fig. 4 Schematic depicting the mechanisms of ceramide action. MFF, mitochondrial fission factor; PKCζ, protein kinase C-zeta; CREB3L1, cAMP responsive element binding protein 3 like 1; PP2A, protein phosphatase 2A; BAX, the pro-apoptotic BCL2 family member BAX; Akt, the serine threonine kinase Akt/PKB; SREBP, sterol response element binding protein; HSL, hormone sensitive lipase.

• 

  Fig. 5 Schematic depicting the interventions that have been shown to ameliorate cardiometabolic disorders. Pharmaceutical interventions or genetic knockout/knockdown of ceramide-synthesizing genes improves insulin sensitivity, resolves hepatic steatosis, and prevents the development of resultant metabolic disorders including diabetes, cardiomyopathy, coronary artery disease, hypertension, and heart failure. Sptlc2, Serine palmitoyltransferase subunit 2; Cers, ceramide synthase genes; Degs1, dihydroceramide desaturase-1 gene; CoA, coenzyme A.

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