Expression of PLTP regulated by NR1H2 or NR1H3

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R-HSA-9624365
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Reaction [omitted]
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Homo sapiens
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The phospholipid transfer protein (PLTP) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PLTP is implicated in cholesterol and phospholipid transfer from triglyceride-rich lipoproteins to HDL during lipolysis by lipoprotein lipase, and in HDL remodeling (formation of β-HDL and large HDL) (Albers JJ et al. 2012; Jiang XC 2018). Beyond its impact on lipoprotein metabolism, PLTP has been reported to modulate inflammation and immune responses (Audo R et al. 2018). PLTP is expressed ubiquitously (Day JR et al. 1994). The highest expression levels in human tissues were observed in ovary, thymus, placenta, and lung (Day JR et al. 1994). Taking into account the organ size involved, liver and small intestine appear to be important sites of PLTP expression (Day JR et al. 1994; Jiang XC et al. 2012). It was also shown that PLTP is highly expressed in macrophages and in atherosclerotic lesions suggesting a potential role for this enzyme in lipid-loaded macrophages (Desrumaux CM et al. 2003; O'Brien KD et al. 2003; Laffitte BA et al. 2003; Vikstedt R et al. 2007). PLTP produced by macrophages may contribute to the optimal function of the ABCA1-mediated cholesterol efflux from macrophages to HDL (Oram JF et al. 2003; Lee-Rueckert M et al. 2006). PLTP is a direct target gene of liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) which form functional heterodimers with the retinoid X receptor (RXR) (Laffitte BA et al. 2003; Mak PA et al. 2002; Cao G et al. 2002). NR1H2 & NR1H3 act as cellular sensors of sterol levels and are transcriptionally activated by oxidized forms of cholesterol, oxysterols (Janowski BA et al. 1996). LXR agonists induced the expression of PLTP in various tissues of mice treated with synthetic LXR agonists, T0901317 or GW3965, in a coordinate manner with known LXR target genes (Cao G et al. 2002; Laffitte BA et al. 2003). PLTP expression was also highly induced by LXR (NR1H2 and NR1H3) and retinoid X receptor (RXR) agonists in murine peritoneal and human THP-1 macrophages (Mak PA et al. 2002; Laffitte BA et al. 2003). Regulation of PLTP by NR1H2 or NR1H3 ligands was abolished in animals or cells lacking both NR1H3 (LXRα) and NR1H2 (LXRβ) (Laffitte BA et al. 2003). Further, administration of the synthetic NR1H2, NR1H3 ligand T0901317 to mice elevated HDL cholesterol and phospholipid and generated enlarged HDL particles that were enriched in cholesterol, ApoAI, ApoE, and phospholipid (Cao G et al. 2002). This occured alongside with the increased plasma PLTP activity and liver PLTP mRNA levels (Cao G et al. 2002). Similar findings were reported for the regulation of PLTP levels in vivo by another synthetic NR1H2, NR1H3 ligand GW3965 (Laffitte BA et al. 2003). These data suggest that NR1H2, NR1H3 and their ligands may modulate plasma lipoprotein metabolism through control of PLTP activity (Laffitte BA et al. 2003; Mak PA et al. 2002; Cao G et al. 2002).

The gene expression of PLTP can be also regulated by other members of the nuclear receptor family of transcription factors: farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor α (PRARα ) (Laffitte BA et al. 2003; Mak PA et al. 2002; Tu AY & Albers JJ 2001).

Literature References
PubMed ID Title Journal Year
12454263 Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors

Mak, PA, Kast-Woelbern, HR, Anisfeld, AM, Edwards, PA

J. Lipid Res. 2002
12612088 The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions

Laffitte, BA, Joseph, SB, Chen, M, Castrillo, A, Repa, JJ, Wilpitz, D, Mangelsdorf, D, Tontonoz, P

Mol. Cell. Biol. 2003
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