Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex. Issue 178 (April 2018)

• Record Type: Journal Article
• Authors: Romano, Simone; Mitro, Nico; Giatti, Silvia; Diviccaro, Silvia; Pesaresi, Marzia; Spezzano, Roberto; Audano, Matteo; Garcia-Segura, Luis Miguel; Caruso, Donatella; Melcangi, Roberto Cosimo
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 178(2017)
• Page Start: 108
• Page End: 116
• Publication Date: 2018-04
• Subjects: HMG-CoA R 3-hydroxy-3-methylglutaryl-coenzyme A reductase -- 3α-diol 5alpha-androstane-3alpha, 17beta-diol -- 3β-diol 5alpha-androstane-3beta, 17beta-diol -- 7α-OH 7α-hydroxycholesterol -- 7β-OH 7β-hydroxycholesterol -- 7-keto 7-ketocholesterol -- 24(S)-OH 24(S)-hydroxycholesterol -- 27-OH 27-hydroxycholesterol -- ATP5A1 α subunit of the mitochondrial ATP synthase F1 complex -- APOE apolipoprotein E -- ABCA1 ATP-binding cassette A1 -- ABCG1 ATP-binding cassette G1 -- mt-COX2 cytochrome c oxidase subunit 2 -- P450scc cytochrome P450 side chain cleavage -- DHEA dehydroepiandrosterone -- DHP dihydroprogesterone -- DHT dihydrotestosterone -- HSL hormone-sensitive lipase -- ISOPREG isopregnanolone -- LC–MS/MS liquid chromatography–tandem mass spectrometry -- LDLR low density lipoprotein receptor -- mt-DNA mitochondrial DNA -- TFAM mitochondrial transcription factor A -- NDUFB8 NADH ubiquinone oxidoreductase subunit 8 -- CTRL non-diabetic rats -- PREG pregnenolone -- PROG progesterone -- OXPHOS respiratory chain complexes functional subunits -- SOD2 superoxide dismutase 2 -- SREBP2 sterol regulatory element-binding protein 2 -- StAR steroidogenic acute regulatory protein -- SOAT1 sterol O-acyltransferase 1 -- STZ streptozotocin -- SDHB succinate dehydrogenase complex iron sulfur subunit B -- T testosterone -- THP tetrahydroprogesterone -- TBARS thiobarbituric acid reactive substances -- TSPO translocator protein-18 kDa -- UQCRC2 ubiquinol-cytochrome c reductase core protein II; Cholesterol -- Mitochondria -- Neuroactive steroids -- Pregnenolone -- Streptozotocin; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.11.009
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: One month of diabetes alters steroidogenic machinery in the cerebral cortex. Impaired cholesterol homeostasis was detected in the cerebral cortex of diabetic rats. Mitochondrial functionality was affected in the cerebral cortex of diabetic rats. Abstract: The nervous system synthesizes and metabolizes steroids (i.e., neurosteroidogenesis). Recent observations indicate that neurosteroidogenesis is affected by different nervous pathologies. Among these, long-term type 1 diabetes, together with other functional and biochemical changes, has been shown to alter neuroactive steroid levels in the nervous system. Using an experimental model of type 1 diabetes (i.e., streptozotocin injection) we here show that the levels of these molecules are already decreased in the rat cerebral cortex after one month of the initiation of the pathology. Moreover, decreased levels of free cholesterol, together with alterations in the expression of molecules involved in cholesterol biosynthesis, bioavailability, trafficking and metabolism were detected in the rat cerebral cortex after one month of diabetes. Furthermore, mitochondrial functionality was also affected in the cerebral cortex and consequently may also contribute to the decrease in neuroactive steroid levels. Altogether, these results indicate that neurosteroidogenesis is an early target for the effect of type 1 diabetes in the cerebral cortex.