被撤回的出版物: Peroxisome Proliferator-Activated Receptor α controls Hepatic Heme Biosynthesis Through ALAS1 (Retracted article. See vol. 404, pg. 172, 2010)

JOURNAL OF MOLECULAR BIOLOGY

卷:388

Article; Retracted Publication

Degenhardt, Tatjana¹  Vaisanen, Sami¹  Rakhshandehroo, Maryam^2,3  Kersten, Sander^2,3  Carlberg, Carsten^1,4 

[1] Univ Kuopio, Dept Biochem, FIN-70211 Kuopio, Finland

[2] Wageningen Univ, Top Inst Food & Nutr, Nutrigenom Consortiton, NL-6701 HD Wageningen, Netherlands

[3] Wageningen Univ, Div Human Nutr, Metab & Genom Grp, NL-6701 HD Wageningen, Netherlands

[4] Univ Luxembourg, Life Sci Res Unit, L-1511 Luxembourg, Luxembourg

关键词: nuclear receptor;    transcriptional regulation;    chromatin;    metabolism;    PPAR alpha;   

DOI  :  10.1016/j.jmb.2009.03.024

来源: Elsevier

【 摘 要 】

Heme is an essential prosthetic group of proteins involved in oxygen transport, energy metabolism and nitric oxide production. ALAS' (5-aminolevulinate synthase) is the rate-limiting enzyme in heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). In primary human hepatocytes and in HepG2 cells, PPAR alpha agonists induced an increase in ALAS1 mRNA levels, which was abolished by PPAR alpha silencing. These effects are mediated by two functional PPAR binding sites at positions -9 and -2.3 kb relative to the ALAS1 transcription start site. PPAR alpha ligand treatment also up-regulated the mRNA levels of the genes ALAD (5-aminolevulinate dehydratase), UROS (uroporphyrinogen III synthase), UROD (uroporphyrinogen decarboxylase), CPOX (coproporphyrinogen oxidase) and PPOX (protoporphyrinogen oxidise) encoding for enzymes controlling further steps in heme biosynthesis. In HepG2 cells treated with PPAR alpha agonists and in mouse liver upon fasting, the association of PPAR alpha, its partner retinoid X receptor, PPAR gamma coactivator 1 alpha and activated RNA polymerase II with the transcription start site region of all six genes was increased, leading to higher levels of the metabolite heme. In conclusion, these data strongly support a role of PPAR alpha in the regulation of human ALAS1 and of five additional genes of the pathway, consequently leading to increased heme synthesis. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

Free