Inhibitors of sphingolipid metabolism are frequently used to investigate the role of ceramide and other sphingolipids as intracellular signaling molecules. For example, the inhibitor of glucosylceramide synthase D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) is commonly used to deplete glycosphingolipids and increase ceramide levels. Ceramide is known to induce growth arrest an...

Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separat...

Title of Document: CERAMIDE PERMEABILIZATION OF MITOCHONDRIAL OUTER MEMBRANE: PHARMACOLOGICAL CHARACTERIZATION AND RELATION TO MAC AND BAX Suzanne J. Hudak, Master of Science, 2005 Directed By: Dr. Marco Colombini, Professor, Biology and Biochemistry Departments In apoptosis, the mitochondrial outer membrane (MOM) becomes permeable, releasing proteins. This permeability has been attributed to t...

OBJECTIVE Ceramide is an important intracellular second messenger that may also increase superoxide. The goal of this study was to determine whether overexpression of CuZn superoxide dismutase (SOD) protects against ceramide-induced increases in vascular superoxide and endothelial dysfunction. METHODS AND RESULTS Carotid arteries from CuZnSOD-transgenic (CuZnSOD-Tg) and nontransgenic litterma...

Recent studies by our group and others have disclosed the presence of ceramides in mitochondria, and the activities of ceramide synthase and reverse ceramidase in mitochondria have also been reported. Since a possible contamination with the ER (endoplasmic reticulum)-related compartment MAM (mitochondria-associated membrane) could not be ruled out in previous studies, we have re-investigated th...

The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR; fenretinide) is cytotoxic to a variety of cancer cell lines, and we previously showed an association between ceramide generation and 4-HPR cytotoxicity for neuroblastoma cell lines (B. J. Maurer et al., J. Natl. Cancer Inst. (Bethesda), 91: 1138-1146, 1999). Here we determine whether the increased ceramide mediated by 4-HPR in the CHLA-90 human...

Ceramide, a sphingolipid metabolite produced by activation of sphingomyelinase, has been previously shown to reduce L-type Ca2+ channel current (ICa,L) in adult rat ventricular myocytes; however, its effect on contractile function is unknown. In this study, we investigated the effects of ceramide on excitation-contraction coupling in adult ventricular myocytes and on left ventricular (LV) funct...

Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids. Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA). We further interfered with the conversion of ceramide into sphingolipids that promote cell growth. Treatment with R-MA led to increased ...

BACKGROUND Evidence indicates that Bax functions as a "lipidic" pore to regulate mitochondrial outer membrane permeabilization (MOMP), the apoptosis commitment step, through unknown membrane elements. Here we show mitochondrial ceramide elevation facilitates MOMP-mediated cytochrome c release in HeLa cells by generating a previously-unrecognized mitochondrial ceramide-rich macrodomain (MCRM), w...

The transport and sorting of lipids are fundamental to membrane biogenesis. In the synthesis of sphingolipids in mammalian cells, ceramide is newly produced at the endoplasmic reticulum (ER), and transported from the ER to the trans Golgi regions, where it is converted to sphingomyelin. Ceramide transfer protein (CERT) mediates the ER-to-Golgi trafficking of ceramide. It has been suggested that...