Review
Hepatic FXR: key regulator of whole-body energy metabolism

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The farnesoid X receptor (FXR) is a nuclear receptor whose activation leads to alterations in pathways involved 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 adipose 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 metabolism of not just bile acids, but also of fats and hydrocarbon metabolites. FXR is currently under study as a therapeutic target for the treatment of diseases of excess, such as diabetes. Here we review the effects of FXR activation in the response of an organism to excess energy.

Section snippets

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, 2, 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], FXRα and FXRβ. FXRα is expressed from a single gene locus in humans and rodents that encodes four different isoforms (resulting from different promoters and RNA

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]. Modulation of FXR activity represents a valid and interesting strategy for combating pernicious effects of several BA-related pathologies, diabetes and other

FXR and lipid metabolism

FXR is an important regulator of lipid metabolism 12, 13, 14, 15, 16. In FXR-deficient mice, serum high-density lipoprotein (HDL) cholesterol and TG levels are elevated, whereas hepatic expression of the HDL receptor scavenger receptor class-B1 (SRB1), which facilitates HDL cholesterol removal from the blood [30], is decreased. FXR also regulates gene expression of proteins involved in lipid metabolism, such as phospholipid transfer protein (PLTP) and apolipoprotein (apo) C-II, which are

Adipokines

Changes in adipose tissue metabolism are intimately related to obesity and insulin resistance. This tissue is responsible for the production of several physiologically active molecules known as adipokines. Examples include leptin, resistin, interleukin (IL)-6, tumor necrosis factor (TNF)-α, plasminogen-activator inhibitor type 1 (PAI-1), resistin and adiponectin (AdipoQ) 41, 42, 43. AdipoQ expression is decreased in obesity, whereas TNF-α, IL-6 and leptin are increased, with mixed reports for

PPARα

FXR regulates the expression of PPARα, a key regulator of lipid metabolism, and its target genes [51]. PPARα agonism increases fatty acid oxidation, lipolysis, energy uncoupling and expenditure, while decreasing lipogenesis, TG secretion and adiposity [52]. Interestingly, there is evidence suggesting that PPARα might activate FXR expression [19], although conflicting evidence remains. For example, in C57BL/6J and KK-Ay mice treated with cholic acid, there was no increase in expression of genes

FXR deficiency in hyperglycemia

FXR expression is decreased in rodent models of diabetes 62, 63. Glucose stimulates FXR expression, whereas insulin represses it [63]. At physiological concentrations, insulin also represses Cyp7a1 [64], which potentially explains the increase in BA synthesis in diabetes that is associated with decreased FXR expression. Taking this into account, it is not surprising that FXR activation leads to decreased glucose levels in wild-type and two diabetic strains (KK-Ay and db/db) of mice 21, 50, 65.

Concluding remarks

Despite being mostly expressed in the liver, FXR is a potent regulator of the metabolic status of an organism. Undoubtedly, FXR agonism causes alterations in several metabolically involved organs where it is not particularly expressed, and changes their energy metabolism profile. Whether it is a positive or negative effect seems to depend on the model used and modus operandi of the experimental procedure. However, the majority of literature seems to point to the fact that FXR activation is

Acknowledgments

J.S. Teodoro is the recipient of a grant from Fundação para a Ciência e a Tecnologia (SFRH/BD/38467/2007).

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