Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter

Abstract

In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXR␣) and LXR␤ as strong activators of the mouse SREBP-1c promoter. Sterol-regulatory element (SRE)-binding proteins (SREBPs) are transcription factors which belong to the basic helix-loophelix leucine zipper family (3-5). In contrast to other members of this family, SREBPs are synthesized as precursor proteins which remain bound to the endoplasmic reticulum and the nuclear envelope in the presence of sufficient sterol concentrations. Upon sterol deprivation, the precursor protein undergoes a sequential two-step cleavage process to release the NH 2 -terminal portion (28). This mature SREBP then enters the nucleus and activates the transcription of genes involved in cholesterol and fatty acid synthesis by binding to SREs or to palindromic sequences called E boxes within their promoter regions (20, 39). Three forms of SREBP have been characterized: SREBP-1a and -1c (also known as ADD1) (14, 38, 43) and SREBP-2. It has been shown that all of the cultured cells analyzed to date express primarily SREBP-2 and the SREBP1a isoform, whereas most organs, including the liver and adipose tissue, express predominantly SREBP-2 and the SREBP1c isoform (36). SREBP-1a is a stronger activator than SREBP-1c due to its longer transactivation domain and has a wider range of target genes involved in both cholesterol and fatty acid synthesis (30, 31).Lipogenic enzymes, which are involved in energy storage through synthesis of fatty acids and triglycerides, are coordinately regulated at the transcriptional level during different metabolic states (9,11). Recent in vivo studies demonstrated that SREBP-1c plays a crucial role in the dietary regulation of most hepatic lipogenic genes, whereas SREBP-2 is actively involved in the transcription of cholesterogenic enzymes (13). These include studies of the effects of the absence or overexpression of SREBP-1 on hepatic lipogenic gene expression (30,31,33), as well as physiological changes of SREBP-1c protein in normal mice after dietary manipulation such as placement on high-carbohydrate diets, polyunsaturated fatty acid-enriched diets, and fasting-refeeding regimens (12,17,37,40,41). The similar coordinated changes in SREBP-1c and lipogenic gene expression upon fasting and refeeding were also observed in adipose tissue (18). In fat tissue, SREBP-1c (ADD1) appears to be involved in adipocyte differentiation and insulin resistance (19,35). Recent studies suggest that insulin or insulin-facilitated glucose uptake mediates lipogenesis through SREBP-1c induction (7,8,10,21,34). Previous reports on the regulation of SREBP-1c have all demonstrated the induction to be at the mRNA level. Up-regulation of hepatic SREBP-1 mRNA was observed in the livers...

The molecular mechanism of the cholesterol‐lowering effect of dill and kale: The influence of the food matrix components

“…Although it has been reported that supplementation with quercetin as a discrete molecule decreases SREBP1c expression both at the protein and mRNA level in primary rat hepatocytes 30 and in mouse adipocytes 31, our results are consistent with the reported increase in liver X receptor (LXR) α expression and activation by quercetin 32, 33. LXR activation potently upregulates SREBF1c expression 34. Phytochemicals other than quercetin in the dill and kale extracts could have synergistically contributed to LXR activation by sustaining its expression to allow it to upregulate SREBF1c expression.…”

A‐FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cells

“…LXR ligands have been shown to activate SREBP-1c expression by inducing binding of LXR to binding sites on the promoter. 48 SREBP-1c has been described as a factor involved in adipocyte differentiation. 49 It has been postulated that deregulation of SREBP controlled gene expression could contribute to cell transformation and tumor development.…”

Thyroid hormone action in metabolic regulation

“…These genes are key regulators of glucose and lipid metabolism. TR has been shown to regulate the transcription of these genes either through TRE or via response elements identified as LXRE or PPRE (Schoonjans et al, 1996;Jansen et al, 2000;Yoshikawa et al, 2001;Araki et al, 2005;Hashimoto et al, 2009;Gauthier et al, 2010). However, most studies were carried out in vitro.…”