title: The thiazolidinedione pioglitazone increases cholesterol biosynthetic gene expression in primary cortical neurons by a PPARgamma-independent mechanism.
abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARgamma agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARgamma antagonist GW9662 did not significantly reduce these effects, suggesting a PPARgamma-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease.
authors.affiliation: Department of Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, Denmark Hill, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Cocks
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Wilde
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Graham
authors.forename: Vicky
authors.initials: V
authors.lastname: Bousgouni
authors.forename: David
authors.initials: D
authors.lastname: Virley
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Jill
authors.initials: J
authors.lastname: Richardson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D002784:Cholesterol; D000077205:Pioglitazone