Hepatic FXR: key regulator of whole-body energy metabolism Joa ˜o Soeiro Teodoro, Anabela Pinto Rolo and Carlos Marques Palmeira Center for Neurosciences and Cell Biology, MitoLab, Department of Life Sciences, University of Coimbra, Coimbra, Portugal The farnesoid X receptor (FXR) is a nuclear receptor whose activation leads to alterations in pathways in- volved in energy metabolism. For example, it serves as a bile acid receptor in tissues such as the liver, and as an energy metabolism regulator in liver, muscle and adi- pose tissue. However, the effects of FXR activation are not exclusive to the tissue where it is present, because receptor crosstalk affects tissues throughout the body. It has been demonstrated that FXR regulates the metabo- lism of not just bile acids, but also of fats and hydrocar- bon metabolites. FXR is currently under study as a therapeutic target for the treatment of diseases of ex- cess, such as diabetes. Here we review the effects of FXR activation in the response of an organism to excess energy. FXR discovery and characterization The farnesoid X receptor (FXR; NR1H4) is a member of the nuclear receptor superfamily and a receptor for bile acids (BAs) [1–3]. FXR binds to FXR response elements [4] either as a monomer or as a heterodimer with the retinoid X receptor (RXR) [5,6] and promotes transcription of target genes. There are two genes encoding FXR [7], FXRa and FXRb. FXRa is expressed from a single gene locus in humans and rodents that encodes four different isoforms (resulting from different promoters and RNA splicing), with different transactivation activities [8]. Whereas FXRa is conserved from fish to humans, FXRb is a pseudogene in humans and is activated by lanosterol [9]. Most genes regulated by FXRa are isoform-independent [7], so for convenience we refer to FXRa (and all its isoforms) simply as FXR hereafter. It should be noted that some FXR target genes are more responsive to particular isoforms; for ex- ample, the intestinal BA-binding protein (IBABP) is more responsive to isoforms a2 and a4 of FXR. However, the physiological relevance of different responsiveness to the different isoforms has yet to be clarified [7]. FXR is mainly expressed in liver, intestine, kidneys and adrenal gland, with less expression in adipose tissue and heart [5,10,11], and was originally identified as a farnesol receptor [5]. Identification of BAs as activators of FXR led to increased interest because of the role of BAs in metabo- lism. The involvement of BAs in lipid metabolism was first evidenced by an increase in hepatic production of very-low- density lipoproteins (VLDL) and serum triglycerides (TG) following therapy with BA sequestrants [12]. Patients with familial hypertriglyceridemia were also found to have deficient ileal BA absorption [13] and work at the time identified use of the FXR ligand chenodeoxycholic acid (CDCA) as a potential anti-lipid agent [14–16]. FXR target genes, their tissue expression and their functions are summarized in Table 1. FXR in disease Diabetes is one of the leading causes of morbidity and mortality in the world (Diabetes Atlas, Regional Overview, http://www.diabetesatlas.com/content/regional-overview). The liver plays a vital role in the maintenance of adequate circulating glucose levels because it is the principal organ for gluconeogenesis and glycogen synthesis [17]. Modula- tion of FXR activity represents a valid and interesting strategy for combating pernicious effects of several BA- related pathologies, diabetes and other complications of the metabolic syndrome [18]. FXR expression increases in fasted mice and is followed by changes in gene expression. For instance, peroxisome proliferator-activated receptor-g (PPARg), PPARg coacti- vator-1a (PGC-1a), and hepatocyte nuclear factor-4a (HNF-4a) were elevated, whereas hepatic lipase (HL) was decreased [19]; the genes that are either directly or indirectly regulated by FXR are important players in metabolism, which highlights the role of FXR in metabo- lism regulation. Overexpression of PGC-1a and cAMP supplementation in rat hepatocytes in vivo and in vitro, respectively, lead to increased FXR expression and activi- ty. It is not surprising then that BAs repress PGC-1a, a mechanism that depends on FXR and small heterodimer partner (SHP, an orphan nuclear receptor) [20–22]. SHP activation inhibits the activity of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), which is re- sponsible for the expression of genes such as cholesterol- 7a-hydroxylase (Cyp7a1) [10,21]; this demonstrates the role of FXR in the regulation of BA synthesis. Other studies have clearly demonstrated that FXR and PGC-1a interact to promote FXR target gene expression [23,24]. PGC-1a is a metabolic trigger and key regulator of metabolic path- ways [25] and cAMP is involved in catabolic pathways of glucose [26], so these studies seem to further suggest that FXR is involved in energy metabolism. Non-alcoholic fatty liver (NAFLD) is a pathology char- acterized by accumulation of fat droplets within hepato- cytes, which can evolve to steatohepatitis and even hepatocellular carcinoma [27]. Patients with NAFLD have lower FXR levels, which has been attributed to increased TG synthesis and expression of liver X receptor (LXR) and the sterol response element binding protein-1c (-SREBF1), Review Corresponding author: Palmeira, C.M. (palmeira@ci.uc.pt). 458 1043-2760/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2011.07.002 Trends in Endocrinology and Metabolism, November 2011, Vol. 22, No. 11