NR1H2 or NR1H3, NRIP1 bind the SREBF1 gene

Stable Identifier
R-HSA-9028525
Type
Reaction [binding]
Species
Homo sapiens
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The oxysterol receptors liver X receptor alpha (LXRα, NR1H3) and LXRβ (NR1H2) were reported to mediate hepatic lipogenesis in rodents and humans by direct binding and upregulation of the sterol regulatory element-binding protein 1c (SREBP1 or SREBF1), which controls the transcription of genes involved in fatty acid (FA) biosynthesis (Schultz JR et al. 2000; Repa JJ et al. 2000; Yoshikawa T et al. 2001). The SREBF1 gene can produce two proteins, SREBP1a and SREBP1c, by use of different promoters (Hua X et al. 1995) and unique first exons (Shimomura I et al. 1997). In humans and mice, the SREBP1c is the predominant SREBF1 isoform in the liver that regulates FA metabolism (Sato R 2010; Horton JD et al. 2002; Shimomura I et al. 1997). NR1H2 & NR1H3 were shown to activate the mouse SREBF1 (SREBP1c) promoter (Repa JJ et al. 2000; Yoshikawa T et al. 2001). In cell transfection studies using human embryonic kidney 293 (HEK293) cells, expression of either NR1H2 or NR1H3 activated the SREBF1 promoter-luciferase reporter gene in a dose-dependent manner (Yoshikawa T et al. 2001). Deletion and mutation studies, as well as gel mobility shift assays, identified two LXREs in the SREBF1 promoter region that regulate expression of SREBP1c by both LXR and RXR agonists (Repa JJ et al. 2000; Yoshikawa T et al. 2001). In mice receiving oral cholesterol, T0901317 (LXR agonist) or LG268 (RXR agonist), SREBP1c mRNA levels are elevated in nearly all tissues tested (Repa JJ et al. 2000). Of note, insulin-mediated transcriptional upregulation of SREBP-1c also maps to the prominent LXRE in this gene promoter, and appears to require LXRs (Chen G. et al. 2004), as well as C/EBPβ (Tian JY et al. 2016) and BHLHE40 (Tian J et al. 2018). In human hepatoma HepG2 cells, SREBF1 mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR:RXR activation can induce endogenous SREBF1 expression (Yoshikawa T et al. 2001). In hepatocytes NRIP1 (RIP140) was reported to act as a coactivator of NR1H2 or NR1H3-induced lipogenesis (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
11287605 Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter

Yoshikawa, T, Shimano, H, Amemiya-Kudo, M, Yahagi, N, Hasty, AH, Matsuzaka, T, Okazaki, H, Tamura, Y, Iizuka, Y, Ohashi, K, Osuga, J, Harada, K, Gotoda, T, Kimura, S, Ishibashi, S, Yamada, N

Mol. Cell. Biol. 2001
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