NR1H2,3, NRIP1 bind the FASN gene

Stable Identifier
R-HSA-9028533
Type
Reaction [binding]
Species
Homo sapiens
Compartment
Synonyms
LXR, NRIP1 bind the FASN gene
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Fatty acid synthase (FAS or FASN) is a central enzyme in de novo lipogenesis and an established target of the sterol regulatory element-binding transcription factor 1 (SREBP1 or SREBF1) pathway. FASN is also induced by agonists of liver X receptor α (LXRα) and LXRβ (also known as NR1H3 and NR1H2, respectively) in various mammalian cells including human monocyte-like THP-1 and hepatocellular carcinoma HepG2 cell lines (Joseph SB et al. 2002; Matsukuma KE et al. 2007). Transient transfection assays showed that sequences located between −700 and −150 bp as well as between −135 and +67 in the FASN promoter mediated the response to NR1H3 and NR1H2 and their synthetic ligands when HepG2 cells were transfected with luciferase reporter constructs containing the rat FAS promoter or a series of 5' deletions in the rat FAS promoter along with expression vectors for NR1H3 and RXRα or NR1H2 and RXRα (Joseph SB et al. 2002). Further, the vast majority of the NR1H2, NR1H3 response was conferred by the sequence between −700 and −150 bp when Hep2G cells were cultured in the presence of high levels of cholesterol or 25-hydroxycholesterol (25-HC), conditions known to suppress SREBP cleavage thus reducing the concentration of nuclear SREBPs to undetectable levels (Joseph SB et al. 2002). A sequence analysis showed that in addition to tandem SREBP sites between −71 and +54, the FASN promoter contains a high affinity LXR response element (LXRE) containing a variant direct-repeat-4 (DR4) motif (between −669 and −655 bp in the rat promoter) that is conserved in diverse animal species including chicken, rat, and humans (Joseph SB et al. 2002). The LXRE and SREBP binding sites independently conferred NR1H3 responsiveness on the FAS promoter, and maximal induction required both SREBP and NR1H3 transcription factors. Gel mobility shift analysis using in vitro translated NR1H3 and RXRα proteins and radiolabeled oligonucleotides confirmed that FASN LXRE binds NR1H3:RXR heterodimers (Joseph SB et al. 2002). These results suggest that NR1H3 regulate FASN expression through direct interaction with an upstream LXRE sequence in the region of FASN promoter as well as indirectly by inducing SREBP1c expression involving sequences between −135 and +67 bp (Joseph SB et al. 2002). Nuclear receptor-interacting protein 1 (NRIP1, also known as receptor-interacting protein 140 (RIP140)) was found to bind directly to the FAS gene promoter in the vicinity of the LXRE and functioned as a positive cofactor for the NR1H2 or NR1H3 - regulated expression of FASN gene in human liver HuH7 cells (Herzog B et al. 2007).

Literature References
PubMed ID Title Journal Year
17684114 The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor

Herzog, B, Hallberg, M, Seth, A, Woods, A, White, R, Parker, MG

Mol. Endocrinol. 2007
11790787 Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors

Joseph, SB, Laffitte, BA, Patel, PH, Watson, MA, Matsukuma, KE, Walczak, R, Collins, JL, Osborne, TF, Tontonoz, P

J. Biol. Chem. 2002
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