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    • At this point it needs however to be

    2022-08-08

    At this point it needs, however, to be mentioned that most in vivo studies regarding the herein discussed nuclear receptors were performed in rodents, especially in mice. Due to the significant differences in metabolism in mice and humans, not all results are translatable between these species and have to be interpreted with caution (Schaap et al., 2014). One major difference between mouse and human metabolism is, for example, that mice lack cholesteryl ester transfer protein (CETP), which, in humans, is responsible for the transfer of cholesteryl esters from high density lipoprotein (HDL) to lipoproteins that contain apolipoprotein (APO) B, like low density lipoprotein (LDL) and very low density lipoprotein (VLDL) (Guyard-Dangremont et al., 1998). This might also be the reason why mice transport the majority of cholesterol in HDL, whereas humans carry most cholesterol in LDL (Bergen and Mersmann, 2005; Camus et al., 1983; Vitic and Stevanovic, 1993). Taking a closer look on LXR, there are some striking differences in the regulation of target genes in rodents versus humans. In mice and rats, the expression of the cytochrome P450 7A1 (CYP7A1), which promotes the rate-limiting step in the conversion of cholesterol to bile acids (Russell and Setchell, 1992), can be regulated by LXR. It was shown that the mouse and rat CYP7A1 promoter contain an LXRE, whereas this does not hold true for humans, meaning that the CYP7A1 promoter cannot be stimulated by LXR (Agellon et al., 2002; Chen et al., 1999; Chiang et al., 2001; Goodwin et al., 2003; Lehmann et al., 1997; Peet et al., 1998). Moreover, CETP, which is not present in mice, is regulated by LXR in humans (Luo and Tall, 2000). In regard to FXR, differences in bile nutlin composition and metabolism are of particular importance. Besides differences in the regulation of bile acid synthesis and conjugation, the bile acid pool in humans is compared to mice more hydrophobic (Chiang, 2009; Heuman, 1989; Russell, 2003; Sanyal et al., 2007). This is particularly relevant because hydrophobic bile acids are good agonists of FXR (Ding et al., 2015). The bile acid pool in mice consists of hydrophilic bile acids like cholic acid (CA) and α-, β- and ω-muricholic acid, which are almost exclusively conjugated with taurine (de Aguiar Vallim et al., 2013). In humans, 40% of the bile acid pool consists of CA, additional 40% of the hydrophobic bile acid chenodeoxycholic acid (CDCA) and 20% of the also hydrophobic deoxycholic acid (DCA) (Li and Chiang, 2014). Interestingly, taurine conjugated α- and β-muricholic acid were identified to be antagonists of FXR (Sayin et al., 2013). Natural products as modulators of these receptors will cover a major part of the review. The possible importance of precision medicine in the context of these nuclear receptors and the therapy of metabolic syndrome-related diseases is finally discussed. For PPARs we refer to several recent reviews giving comprehensive overviews regarding this topic (Gross et al., 2017; Rigano et al., 2017; Wang et al., 2014).
    The liver X receptor (LXR) The liver X receptor exists in two isoforms, LXRα and LXRβ. LXRα (also known as NR1H3) is expressed in metabolically active tissues, like the liver, adipose, kidney, macrophages and intestines, whereas LXRβ (or NR1H2) is expressed ubiquitously (Apfel et al., 1994; Repa and Mangelsdorf, 2000; Willy et al., 1995). As type 2 nuclear receptors, LXRs form heterodimers with RXR. These heterodimers belong to the so-called permissive heterodimers, meaning that the receptor dimer can be activated either by ligands for LXR or RXR, or even by both synergistically (Willy et al., 1995). Endogenous ligands of the LXR/RXR heterodimer are oxysterols, which are oxygenated derivatives of cholesterol and intermediate metabolites of cholesterol biosynthesis (Janowski et al., 1999; Janowski et al., 1996; Schroepfer Jr, 2000). Ligand activation of LXR leads to the recruitment of specific coactivators (e.g. steroid receptor coactivator-1 (SRC-1)), which, for instance, induce a change in local chromatin architecture via histone acetylation, finally resulting in the transcription of target genes (Janowski et al., 1999; Wagner et al., 2003).