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Review
. 2011 Nov;121(11):4222-30.
doi: 10.1172/JCI57144. Epub 2011 Nov 1.

Ceramides as Modulators of Cellular and Whole-Body Metabolism

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Free PMC article
Review

Ceramides as Modulators of Cellular and Whole-Body Metabolism

Benjamin T Bikman et al. J Clin Invest. .
Free PMC article

Abstract

Nearly all stress stimuli (e.g., inflammatory cytokines, glucocorticoids, chemotherapeutics, etc.) induce sphingolipid synthesis, leading to the accumulation of ceramides and ceramide metabolites. While the role of these lipids in the regulation of cell growth and death has been studied extensively, recent studies suggest that a primary consequence of ceramide accumulation is an alteration in metabolism. In both cell-autonomous systems and complex organisms, ceramides modify intracellular signaling pathways to slow anabolism, ensuring that catabolism ensues. These ceramide actions have important implications for diseases associated with obesity, such as diabetes and cardiovascular disease.

Figures

Figure 1
Figure 1. Ceramide can be produced by three pathways.
De novo ceramide synthesis depends on the availability of palmitate and serine, while sphingomyelin hydrolysis and ceramide salvage both require an initial supply of ceramide. Ss, sphingosine.
Figure 2
Figure 2. Ceramide biosynthesis and degradation require specific signals and impart disparate effects.
(A) Activation of adiponectin receptors 1 and 2 (AdipoR 1/2) induces synthesis of sphingosine and S1P, which induces an improved metabolic state, characterized by improved insulin sensitivity, reduced inflammation, and AMPK activation. (B) In contrast, activation of TLR4 initiates an inflammatory cascade essential to ceramide biosynthesis and metabolic impingement.
Figure 3
Figure 3. Ceramide accumulation inhibits Akt activation.
Central to ceramide’s antianabolic effects is its potent inhibition of Akt, resulting in reduced nutrient uptake and progrowth signaling. SFA, saturated fatty acid; LBP, LPS-binding protein.

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