Direct and Indirect Mechanisms for Regulation of Fatty Acid Synthase Gene Expression by Liver X Receptors*

By S. Joseph, B. Laffitte, Parthive H. Patel, M. Watson, K. Matsukuma, R. Walczak, J. Collins, T. Osborne, P. Tontonoz. Journal of Biological Chemistry, 2002

800 citations recorded by the source corpus.

The nuclear receptors LXRα and LXRβ have been implicated in the control of lipogenesis and cholesterol homeostasis. Ligand activation of these receptors in vivoinduces expression of the LXR target gene SREBP-1cand increases plasma triglyceride levels. Expression of fatty acid synthase (FAS), a central enzyme in de novo lipogenesis and an established target of the SREBP-1 pathway, is also induced by LXR ligands. The effects of LXR ligands on FAS expression have been proposed to be entirely secondary to the induction of SREBP-1c. We demonstrate here that LXRs regulate FAS expression through direct interaction with the FAS promoter as well as through activation of SREBP-1c expression. Induction of FAS expression in HepG2 cells by LXR ligands is reduced, but not abolished, under conditions where SREBP processing is suppressed. Moreover, LXR ligands induce FAS expression in CHO-7 cells without altering expression of SREBP-1. We demonstrate that in addition to tandem SREBP sites, the FASpromoter contains a high affinity binding site for the LXR/RXR heterodimer that is conserved in diverse animal species including birds, rodents, and humans. The LXR and SREBP binding sites independently confer LXR responsiveness on the FASpromoter, and maximal induction requires both transcription factors. Transient elevation of plasma triglyceride levels in mice treated with a synthetic LXR agonist correlates with transient induction of hepatic FAS expression. These results indicate that the LXR signaling pathway modulates FAS expression through distinct but complementary mechanisms and suggest that the FAS gene may be a critical target in the control of lipogenesis by LXRs.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/b2aa0b7fc0d9aab55d794416bbbe2d308e40cc86

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Oncology

In Surgery

Citations in the corpus

PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. (2008, background): “As an important control, only RXR was recruited to the LXR response element in the fatty acid synthase promoter (Joseph et al. 2002; Matsukuma et al. 2007), which PPAR does not bind (Supplemental Fig.”
The role of FoxO in the regulation of metabolism (2008, background): “Other factors, including liver X receptor, which also stimulates SREBP-1c expression, directly induce the transcription of lipogenic genes as well (Joseph et al., 2002; Tobin et al., 2002).”
Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. (2006, background): “Signaling through RXR:PPARγ, RXR:LXR and ADD1/Srebf1 in hepatocytes has been shown to modulate fatty acid synthesis through transcriptional control of acetyl-CoA carboxylase (Acac), the rate limiting step in long chain fatty acid synthesis (48, 49), as well as fatty acid synthase (Fasn) (50-53).”
Liver X receptor signaling pathways in cardiovascular disease. (2003, background): “From a drug development standpoint, the most desirable LXR agonist would be one that was a strong inducer of ABCA1 and a strong suppressor of inflammatory gene expression yet lacked activity on the SREBP-1c and FAS promoters.”