title: Chronic caloric restriction attenuates a loss of sulfatide content in PGC-1α-/- mouse cortex: a potential lipidomic role of PGC-1α in neurodegeneration.
abstract: Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a key regulator of energy metabolism and lipid homeostasis in multiple highly oxidative tissues, has been implicated in the metabolic derangements of diabetes and obesity. However, relatively less is known regarding its role in neurological functions. Using shotgun lipidomics, we investigated the lipidome of mouse cerebral cortex with generalized deficiency of PGC-1α (PGC-1α(-/-)) versus wild-type (WT) mice under standard diet and chronically calorically restricted conditions. Specific deficiency in sulfatide, a myelin-specific lipid class critically involved in maintaining neurological function, was uncovered in the cortex of PGC-1α(-/-) mice compared with WT mice at all ages examined. Chronic caloric restriction (CR) for 22 months essentially restored the sulfatide reduction in PGC-1α(-/-) mice compared with WT, but sulfatide reduction was not restored in PGC-1α(-/-) with CR for a short term (i.e., 3 months). Mechanistic studies uncovered and differentiated the biochemical mechanisms underpinning the two conditions of altered sulfatide homeostasis. The former is modulated through PGC-1α-MAL pathway, whereas the latter is under the control of LXR/RXR-apoE metabolism pathway. These results suggest a novel mechanistic role of PGC-1α in sulfatide homeostasis, provide new insights into the importance of PGC-1α in neurological functions, and indicate a potential therapeutic approach for treatment of deficient PGC-1α-induced alterations in sulfatide homeostasis.
authors: Division of Bioorganic Chemistry and Molecular Pharmacology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Michael A
authors: MA
authors: Kiebish
authors: Dee M
authors: DM
authors: Young
authors: John J
authors: JJ
authors: Lehman
authors: Xianlin
authors: X
authors: Han
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D031204:Caloric Restriction; D002540:Cerebral Cortex / Q000378:metabolism*; D002553:Cerebroside-Sulfatase / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009185:Myelin Proteins / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D019636:Neurodegenerative Diseases / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011510:Proteolipids / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D001057:Apolipoproteins E; D004798:Enzymes; D000071518:Liver X Receptors; C569027:Mal protein, mouse; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D057093:Orphan Nuclear Receptors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011510:Proteolipids; D047488:Retinoid X Receptors; D013433:Sulfoglycosphingolipids; D015534:Trans-Activators; D014157:Transcription Factors; D015238:Sulfotransferases; C020556:galactosylceramide sulfotransferase; D002553:Cerebroside-Sulfatase