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Role of ceramide in diabetes mellitus: evidence and mechanisms.

Galadari S, Rahman A, Pallichankandy S, Galadari A, Thayyullathil F - Lipids Health Dis (2013)

Bottom Line: Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt.Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance.Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Cell Signaling Laboratory, College of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain, Abu Dhabi, United Arab Emirates. sehamuddin@uaeu.ac.ae

ABSTRACT
Diabetes mellitus is a metabolic disease with multiple complications that causes serious diseases over the years. The condition leads to severe economic consequences and is reaching pandemic level globally. Much research is being carried out to address this disease and its underlying molecular mechanism. This review focuses on the diverse role and mechanism of ceramide, a prime sphingolipid signaling molecule, in the pathogenesis of type 1 and type 2 diabetes and its complications. Studies using cultured cells, animal models, and human subjects demonstrate that ceramide is a key player in the induction of β-cell apoptosis, insulin resistance, and reduction of insulin gene expression. Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt. Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance. Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression. Better understanding of this area will increase our understanding of the contribution of ceramide to the pathogenesis of diabetes, and further help in identifying potential therapeutic targets for the management of diabetes mellitus and its complications.

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Regulation of sphingolipid biosynthesis. Details of these processes and abbreviations are described in the text. Briefly, ceramide is formed from L-serine and palmitoyl CoA via de novo pathway. Ceramide can also be formed from SM hydrolysis by SMase, glucosyl ceramide hydrolysis by Glucocerebrosidase and from sphingosine by ceramide synthase. Sphingolipid metabolites are depicted in box and enzymes are shown outside the box. Some pharmacological inhibitors of sphingolipid biosynthetic enzymes are also shown.
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Figure 2: Regulation of sphingolipid biosynthesis. Details of these processes and abbreviations are described in the text. Briefly, ceramide is formed from L-serine and palmitoyl CoA via de novo pathway. Ceramide can also be formed from SM hydrolysis by SMase, glucosyl ceramide hydrolysis by Glucocerebrosidase and from sphingosine by ceramide synthase. Sphingolipid metabolites are depicted in box and enzymes are shown outside the box. Some pharmacological inhibitors of sphingolipid biosynthetic enzymes are also shown.

Mentions: The biosynthetic pathway of sphingolipids consists of a complex network of synthetic and degradative reactions. The de novo biosynthesis of sphingolipids occurs at the cytosolic leaflet of the endoplasmic reticulum (ER). During this, 3-ketosphinganine is formed by the condensation of L-serine and palmitoyl CoA by the action of an enzyme serine palmitoyl transferase (SPT). The newly formed 3-ketosphinganine first undergoes rapid reduction to dihydrosphingosine by the action of 3-ketosphinganine reductase, which is then acetylated to form dihydroceramide (dh-Cer) by the action of dh-Cer synthase. The enzyme dh-Cer desaturase reduces dh-Cer to ceramide (Figure 2)[4,5,17]. Ceramide serves as a ‘metabolic hub’ in the sphingolipid metabolic pathway as a substrate for subsequent production of other sphingolipid signaling intermediates[18-20]. Neutral ceramidase in the ER, alkaline ceramidase in the plasma membrane, and acid ceramidase in the lysosome may hydrolyze ceramide to generate sphingosine. Sphingosine may be phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinase. The formation of sphingosine from ceramide and S1P from sphingosine can be reversed by enzymes ceramide synthase and S1P phosphatase respectively (Figure 2).


Role of ceramide in diabetes mellitus: evidence and mechanisms.

Galadari S, Rahman A, Pallichankandy S, Galadari A, Thayyullathil F - Lipids Health Dis (2013)

Regulation of sphingolipid biosynthesis. Details of these processes and abbreviations are described in the text. Briefly, ceramide is formed from L-serine and palmitoyl CoA via de novo pathway. Ceramide can also be formed from SM hydrolysis by SMase, glucosyl ceramide hydrolysis by Glucocerebrosidase and from sphingosine by ceramide synthase. Sphingolipid metabolites are depicted in box and enzymes are shown outside the box. Some pharmacological inhibitors of sphingolipid biosynthetic enzymes are also shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716967&req=5

Figure 2: Regulation of sphingolipid biosynthesis. Details of these processes and abbreviations are described in the text. Briefly, ceramide is formed from L-serine and palmitoyl CoA via de novo pathway. Ceramide can also be formed from SM hydrolysis by SMase, glucosyl ceramide hydrolysis by Glucocerebrosidase and from sphingosine by ceramide synthase. Sphingolipid metabolites are depicted in box and enzymes are shown outside the box. Some pharmacological inhibitors of sphingolipid biosynthetic enzymes are also shown.
Mentions: The biosynthetic pathway of sphingolipids consists of a complex network of synthetic and degradative reactions. The de novo biosynthesis of sphingolipids occurs at the cytosolic leaflet of the endoplasmic reticulum (ER). During this, 3-ketosphinganine is formed by the condensation of L-serine and palmitoyl CoA by the action of an enzyme serine palmitoyl transferase (SPT). The newly formed 3-ketosphinganine first undergoes rapid reduction to dihydrosphingosine by the action of 3-ketosphinganine reductase, which is then acetylated to form dihydroceramide (dh-Cer) by the action of dh-Cer synthase. The enzyme dh-Cer desaturase reduces dh-Cer to ceramide (Figure 2)[4,5,17]. Ceramide serves as a ‘metabolic hub’ in the sphingolipid metabolic pathway as a substrate for subsequent production of other sphingolipid signaling intermediates[18-20]. Neutral ceramidase in the ER, alkaline ceramidase in the plasma membrane, and acid ceramidase in the lysosome may hydrolyze ceramide to generate sphingosine. Sphingosine may be phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinase. The formation of sphingosine from ceramide and S1P from sphingosine can be reversed by enzymes ceramide synthase and S1P phosphatase respectively (Figure 2).

Bottom Line: Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt.Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance.Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Cell Signaling Laboratory, College of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain, Abu Dhabi, United Arab Emirates. sehamuddin@uaeu.ac.ae

ABSTRACT
Diabetes mellitus is a metabolic disease with multiple complications that causes serious diseases over the years. The condition leads to severe economic consequences and is reaching pandemic level globally. Much research is being carried out to address this disease and its underlying molecular mechanism. This review focuses on the diverse role and mechanism of ceramide, a prime sphingolipid signaling molecule, in the pathogenesis of type 1 and type 2 diabetes and its complications. Studies using cultured cells, animal models, and human subjects demonstrate that ceramide is a key player in the induction of β-cell apoptosis, insulin resistance, and reduction of insulin gene expression. Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt. Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance. Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression. Better understanding of this area will increase our understanding of the contribution of ceramide to the pathogenesis of diabetes, and further help in identifying potential therapeutic targets for the management of diabetes mellitus and its complications.

Show MeSH
Related in: MedlinePlus