Endogenous levels of 1-O-acylceramides increase upon acidic ceramidase deficiency and decrease due to loss of Dgat1 in a tissue-dependent manner.

Abstract

Except for epidermis and liver, little is known about endogenous expression of 1-O-acylceramides (1-OACs) in mammalian tissue. Therefore, we screened several organs (brain, lung, liver, spleen, lymph nodes, heart, kidney, thymus, small intestine, and colon) from mice for the presence of 1-OACs by LC-MS2. In most organs, low levels of about 0.25-1.3 pmol 1-OACs/mg wet weight were recorded. Higher levels were detected in liver, small and large intestines, with about 4-13 pmol 1-OACs/mg wet weight. 1-OACs were esterified mainly with palmitic, stearic, or oleic acids. Esterification with saturated very long-chain fatty acids, as in epidermis, was not observed. Western-type diet induced 3-fold increased 1-OAC levels in mice livers while ceramides were unaltered. In a mouse model of Farber disease with a decrease of acid ceramidase activity, we observed a strong, up to 50-fold increase of 1-OACs in lung, thymus, and spleen. In contrast, 1-OAC levels were reduced 0.54-fold in liver. Only in lung 1-OAC levels correlated to changes in ceramide levels - indicating tissue-specific mechanisms of regulation. Glucosylceramide synthase deficiency in liver did not cause changes in 1-OAC or ceramide levels, whereas increased ceramide levels in glucosylceramide synthase-deficient small intestine caused an increase in 1-OAC levels. Deficiency of Dgat1 in mice resulted in a reduction of 1-OACs to 30% in colon, but not in small intestine and liver, going along with constant free ceramides levels. From these data, we conclude that Dgat1 as well as lysosomal lipid metabolism contribute in vivo to homeostatic 1-OAC levels in an organ-specific manner.

• Authors: Aline Bayerle, Christian Marsching, Mariona Rabionet, Shaalee Dworski, Mustafa A Kamani, Chandramohan Chitraju, Nina L Gluchowski, Katlyn R Gabriel, Silke Herzer, Richard Jennemann, Thierry Levade, Jeffrey A Medin, Roger Sandhoff
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1865 Issue 9 Pg. 158741 (09 2020) ISSN: 1879-2618 [Electronic] Netherlands
• PMID: 32474112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Ceramides
• Dgat1 protein, mouse
• Diacylglycerol O-Acyltransferase

Topics

• Animals
• Brain (metabolism)
• Ceramides (metabolism)
• Colon (metabolism)
• Diacylglycerol O-Acyltransferase (metabolism)
• Farber Lipogranulomatosis (metabolism)
• Intestine, Small (metabolism)
• Kidney (metabolism)
• Lipid Metabolism
• Liver (metabolism)
• Lung (metabolism)
• Lymph Nodes (metabolism)
• Male
• Mice, Inbred C57BL
• Myocardium (metabolism)
• Spleen (metabolism)
• Thymus Gland (metabolism)