**The Role of Liver X Receptor in Hepatic** *de novo* **Lipogenesis and Cross-Talk with Insulin and Glucose Signaling**

Line M. Grønning-Wang, Christian Bindesbøll and Hilde I. Nebb

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51357

### **1. Introduction**

60 Lipid Metabolism

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Regulation of nutrient balance by the liver is important to ensure whole body metabolic control. Hepatic expression of genes involved in lipid and glucose metabolism is tightly regulated in response to nutritional cues, such as glucose and insulin. In response to dietary carbohydrates, the liver converts excess glucose into fat for storage through *de novo* lipogenesis. The liver X receptors (LXRα and LXRβ) are important transcriptional regulators of this process. LXRs are classically known as oxysterol sensing nuclear receptors that heterodimerize with the retinoic X receptor (RXR) family and activate transcription of nutrient sensing transcription factors such as sterol regulatory element-binding protein 1c (SREBP1c) (Repa et al., 2000; Yoshikawa et al., 2002; Liang et al., 2002) and carbohydrate response element-binding protein (ChREBP) (Cha & Repa, 2007). LXR also induces the transcription of the lipogenic enzyme genes fatty acid synthase (FAS), stearoyl-Coenzyme A desaturase (SCD1) and Acetyl CoA carboxylase (ACC), alone or in concert with SREBP1c and/or ChREBP (Chu et al., 2006; Joseph et al., 2002; Talukdar & Hillgartner, 2006). LXR activate transcription of hepatic lipogenic genes in response to feeding, which is believed to be mediated by insulin (Tobin et al., 2002). The mechanisms by which insulin activates LXRmediated gene expression is not clearly understood, but may involve production of endogenous ligand for LXRs and/or act by signal transduction mechanisms downstream of the insulin receptor (IR). Both glucose and insulin regulate *de novo* lipogenesis, however, some lipogenic genes can be regulated by glucose without the need of insulin which has been shown for SREBP1c (Hasty et al., 2000; Matsuzaka et al., 2004). A well known glucosemediator in liver is ChREBP, an important regulator of *de novo* lipogenesis in response to glucose (Yamashita et al., 2001). ChREBP is activated by glucose via hexose- and pentosephosphate-dependent mechanisms involving dephosphorylation of ChREBP and

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translocation to the nucleus (Havula & Hietakangas, 2012). Interestingly, both LXR and ChREBP were recently shown to be post-translationally modified by O-linked -Nacetylglucosamine (O-GlcNAc) in response to glucose potentiating their lipogenic capacity (Anthonisen et al., 2010; Guinez et al., 2011). Glucose flux through the hexosamine signaling pathway generates UDP-N-acetyl-glucosamine (UDP-GlcNAc), a substrate for O-GlcNAc modification of nucleocytoplasmic proteins by the enzyme O-GlcNAc transferase (OGT). We have shown that O-GlcNAcylation of LXR is increased in mouse livers in response to feeding and in livers from hyperglycemic diabetic mice potentiating SREBP1c expression (Anthonisen et al., 2010). Furthermore, preliminary studies in our laboratory indicate that LXR potentiate ChREBP activity under hyperglycemic conditions establishing a link between glucose metabolism, LXR and ChREBP. These observations suggest that LXR, SREBP1c and ChREBP contribute to converting carbohydrates into fat in a cooperative manner in response to high circulating glucose levels and that O-GlcNAc signaling plays a role in this process. As O-GlcNAc cycling appear to be essential for proper insulin signaling and the sensitivity of OGT to glucose increases with decreasing insulin signaling (Mondoux et al., 2011; Hanover et al., 2010) the relative roles of LXR, SREBP1c and ChREBP in regulating *de novo* lipogenesis in response to feeding and modification by O-GlcNAc signaling under insulin sensitive and insulin resistant conditions will be discussed.

The Role of Liver X Receptor in Hepatic *de novo* Lipogenesis and Cross-Talk with Insulin and Glucose Signaling 63

The DNA-binding domain (DBD) and the ligand binding domain (LBD) are highly structured domains. LXRα and LXRβ share 78 % amino acid sequence identity in these regions, while the N-terminal domain (NTD) and the hinge domain are far more disordered and less conserved. DNA binding requires dimerization with RXR. Transactivation by the LXRs is mediated through the ligand independent activation function (AF1) in NTD and the ligand dependent activation function 2 (AF2) in the LBD. Binding of a ligand to the hydrophobic ligand binding pocket leads to a conformational change that releases corepressors (CR) and exposes binding sites for coactivators (CA), recruiting the general transcription machinery and RNA polymerase II (RNA Pol II) (Fig. 2). This leads to changes in LXR dependent gene expression. The interactions with coregulators can also occur independently of ligand to AF1, however this is far less characterized. Upon activation, LXRs regulate a number of genes involved in lipid, cholesterol and glucose metabolism by binding to LXR response elements (LXREs) in their promoter region. These consist of a direct repeat of the nucleotide hexamer AGGTCA spaced by four nucleotides. Insights into LXR function in metabolism was provided by the generation of LXR mutant mice. These mice accumulate hepatic cholesterol, ultimately causing liver dysfunction (Peet et al., 1998; Ulven et al., 2005). It was found that LXRcontrols cholesterol metabolism by conversion of cholesterol to bile acid by induction of the cholesterol 7 alpha-hydroxylase (Cyp7A1) gene, biliary cholesterol excretion and cholesterol efflux via induction of ABCG5/8 and ABCA1/ABCG1, respectively (Lehmann et al., 1997; Chiang et al., 2001; Yu et al., 2003; Repa et al., 2002; Graf et al., 2002; Costet et al., 2000; Sabol et al., 2005; Venkateswaran et al., 2000; Venkateswaran et al., 2000). LXRs are strongly implicated in the development of metabolic disorders and associated pathologies, notably, hyperlipidemia and atherosclerosis (Peet et al., 1998; Calkin & Tontonoz, 2010). Thus, LXRs are key players in maintaining metabolic homeostasis in health and disease by regulating inflammation and lipid/carbohydrate

metabolism.

**Figure 2.** Activation of LXR by coregulator switching

**2.2. Modulation of LXR activity by coregulators and PTMs** 

The transcriptional activity of LXRs is highly dependent on the presence of coregulators which has been linked to several metabolic processes (Jakobsson et al., 2009; Kim et al., 2003; Huuskonen et al., 2004; Kim et al., 2008; Oberkofler et al., 2003). Coregulators constitutes large multisubunit protein complexes containing chromatin-remodelling and/or –modifying
