Pathological roles of ceramide and its metabolites in metabolic syndrome and Alzheimer's disease.
The public health burden of metabolic syndrome (MetS), a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose conditions, and Alzheimer's disease (AD), the most common form of dementia, continues to expand. Current available therapies for these disorders are of limited effectiveness. Recent findings have indicated that alternations in sphingolipid metabolism contribute to the development of these pathologies. Sphingolipids are major constituents of the plasma membrane, where they are known to form several types of microdomains, and are potent regulators for a variety of physiological processes. Many groups, including ours, have demonstrated that membrane sphingolipids, especially ceramide and its metabolites such as ceramide 1-phosphate, have roles in arteriosclerosis, obesity, diabetes, and inflammation associated with MetS. Aberrant sphingolipid profiles have been observed in human AD brains, and accumulated evidence has demonstrated that changes in membrane properties induced by defective sphingolipid metabolism impair generation and degradation of amyloid-β peptide (Aβ), a pathogenic agent of AD. In this review, we summarize current knowledge and pathophysiological implications of the roles of SLs in MetS and AD, to provide insight into the SL metabolic pathways as potential targets for therapy of these diseases. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
Kohei
K
Yuyama
Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan. Electronic address: susumu-m@pharm.hokudai.ac.jp.
Susumu
S
Mitsutake
Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
Yasuyuki
Y
Igarashi
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D002518:Ceramides / Q000378:metabolism*; D006801:Humans; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology*
D002518:Ceramides
Alzheimer's disease; Ceramide; Glycosphingolipid; Metabolic syndrome; Sphingolipid; Sphingomyelin