Lipids Signaling

Author: Gianpiero Pescarmona
Date: 01/02/2011


Central role of Ceramide


Schematic representation of mechanism of beta-cell apoptosis caused by ceramide. Details of the processes and abbreviations are described in the text. Briefly, cellular ceramide can be formed by de novo biosynthesis from precursor palmitate and by the activation of extrinsic pathway of apoptosis by FasL or TNF-α binding to the Fas and TNF receptor (TNFR) respectively. Ceramide acts on the mitochondria and causes the release of ROS/RNS and cytochrome c and activates intrinsic apoptotic pathway. Increased ROS can further increase ceramide generation. Ceramide can act on the ER and cause ER stress mediated apoptosis. Ceramide also inhibits insulin gene expression. (Role of ceramide in diabetes mellitus: Evidence and mechanisms, 2013


ceramide as a proapoptotic stimulus

Ceramide synthesis

2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length.2008
These results suggest that all CerS members can synthesize 2-hydroxy-CER with specificity for 2-hydroxy-fatty acyl-CoA chain length and that CerS3 may be important in CER and 2-hydroxy-CER synthesis in epidermis.

Brenda 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase2=Fatty+acid+2-hydroxylase&T2=2&V8=1



DESCRIPTION (provided by applicant): In higher vertebrates, nerve conduction is greatly facilitated by myelin, a lipid-rich membrane that wraps around the axon. A number of devastating demyelinating diseases threat human health, and few effective treatments exist. To develop better treatment for these diseases, we must understand the mechanisms involved in myelination. Myelin is a specialized structure with distinct lipid and protein constituents. Galactosylceramide (GalCer) and sulfatide make up approximately 30% of total myelin lipids, and more than half of these galactolipids contain fatty acid with a hydroxyl group at the C2 position (2-OH galactolipids). No other mammalian tissues contain such high concentrations of 2-OH fatty acids, suggesting that 2-OH galactolipids may play a crucial role in creating the special characteristics of myelin. Despite the extraordinary abundance of 2-OH galactolipids in myelin, there is surprisingly little understanding of the basic biochemistry and physiological role of 2-OH galactolipids. The overall goal of this study is to elucidate the pathway for myelin 2-OH lipids and their roles in myelination, myelin function, and cell signaling. A recently identified fatty acid 2-hydroxylase, FA2H, provides the precursor for the synthesis of myelin 2- OH galactolipids in oligodendrocytes and Schwann cells. FA2H and other enzymes are responsible for the increase in 2-OH very-long-chain (>C20) fatty acid contents in galactolipids during myelination. The first aim of this project is to establish the biosynthetic pathway involved in the unique lipid compositions of myelin galactolipids. Extensive biochemical analyses of FA2H will be performed to determine its physiological substrate, cofactors, and potential feedback mechanisms. Isoforms of fatty acid elongases and dihydroceramide synthases will be identified by a molecular genetic approach. More recently, it was found that reduced FA2H expression via RNAi significantly enhanced motility of D6P2T cells. Cellular 2-OH also partially blocked the upregulation of cyclin-dependent kinase inhibitors, p21 and p27, in response to a stimulus for differentiation. These observations indicate that 2-OH lipids are not only major structural components of myelin, but also function as signaling molecules to modulate cell differentiation and motility. In the second aim, the mechanism of action of 2-OH lipids in cell differentiation and motility will be determined. Transcriptional regulation for p21 and p27 will be investigated to determine the target protein modulated by 2-OH lipids, and the molecular identity of 2-OH lipid species with signaling function will be determined. The third aim is to determine the role of 2-OH galactolipids in myelin function and remyelination in adult brain. The cuprizone- induced demyelination/remyelination will be used to show FA2H is involved in remyelination. Subsequently, newly available conditional FA2H-knockout mice will be used to inactivate FA2H in adult brain. This model will be used to investigate myelin morphology, function, and remyelination in the absence of 2-OH lipids. PUBLIC HEALTH RELEVANCE To develop better treatment for devastating demyelinating diseases, we must understand the mechanisms involved in myelination. This project seeks to unravel the complex pathways for the synthesis of myelin lipids and their roles in myelin maintenance and function, as well as in cell signaling that controls proper myelination. Results obtained from this study will aid in developing better therapeutic agents for neurodegenerative diseases, such as multiple sclerosis.

Project leader Hama Hiroko Projects

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Hama Hiroko su research gate

E-mail: hama@musc.edu

Quetzal Hama Hiroko

Ceramide Signaling

Dropping acid to help cystic fibrosis, 2008

Ceramide in the skin barrier

Biochim Biophys Acta. 2006 Dec;1758(12):2080-95. Epub 2006 Jul 11.
The skin barrier in healthy and diseased state., 2006

The primary function of the skin is to protect the body for unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. The stratum corneum consists of corneocytes surrounded by lipid regions. As most drugs applied onto the skin permeate along the lipid domains, the lipid organization is considered to be very important for the skin barrier function. It is for this reason that the lipid organization has been investigated quite extensively. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid organization is different from that of other biological membranes. In stratum corneum, two lamellar phases are present with repeat distances of approximately 6 and 13 nm. Moreover the lipids in the lamellar phases form predominantly crystalline lateral phases, but most probably a subpopulation of lipids forms a liquid phase. Diseased skin is often characterized by a reduced barrier function and an altered lipid composition and organization. In order to understand the aberrant lipid organization in diseased skin, information on the relation between lipid composition and organization is crucial. However, due to its complexity and inter-individual variability, the use of native stratum corneum does not allow detailed systematic studies. To circumvent this problem, mixtures prepared with stratum corneum lipids can be used. In this paper first the lipid organization in stratum corneum of normal and diseased skin is described. Then the role the various lipid classes play in stratum corneum lipid organization and barrier function has been discussed. Finally, the information on the role various lipid classes play in lipid phase behavior has been used to interpret the changes in lipid organization and barrier properties of diseased skin.

Biologically active sphingolipids in cancer pathogenesis and treatment, 2004

Ceramide and apoptosis

SK1 activation by various agonists (PDGF, EGF, VEGF, bFGF, IGF, NGF, TGF- β , TNF- α , interleukins and hormones) via their receptor is followed by SK1 translocation to the plasma membrane to generate S1P from sphingosine.
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Figure and captions

Ceramide analogues induce apoptosis in human cancer cells [50,51], and the inhibitor of acid ceramidase, an enzyme that promotes ceramide degradation, stimulates accumulation of ceramide, preventing tumor growth

Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance 2014

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