Regulation of Carbohydrate Metabolism by the Farnesoid X Receptor

Abstract

The farnesoid X receptor (FXR; NR1H4) is a nuclear hormone receptor that functions as the bile acid receptor. In addition to the critical role FXR plays in bile acid metabolism and transport, it regulates a variety of genes important in lipoprotein metabolism. We demonstrate that FXR also plays a role in carbohydrate metabolism via regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Treatment of either H4IIE or MH1C1 rat hepatoma cell lines as well as primary rat or human hepatocytes with FXR agonists led to stimulation of PEPCK mRNA expression to levels comparable to those obtained with glucocorticoid receptor agonists. We examined the physiological significance of FXR agonist-induced enhancement of PEPCK expression in primary rat hepatocytes. In addition to inducing PEPCK expression in primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a glucocorticoid receptor agonist. Consistent with these observations, treatment of C57BL6 mice with GW4064 significantly increased hepatic PEPCK expression. Activation of FXR initiated a cascade involving induction of peroxisome proliferator-activated receptor alpha and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of Forkhead/winged helix transcription factor (FOXO1). The FXR-peroxisome proliferator-activated receptor alpha-TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as primary human hepatocytes. Thus, in addition to its role in the regulation of lipid metabolism, FXR regulates carbohydrate metabolism.

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

“…FXR activation increases Ppeck expression via a mechanism that involves PPAR␣ and as such could have a negative impact on glucose homeostasis (35). As discussed before, short term treatment with GW4064, however, improves or does not change glucose homeostasis again indicating that after long term GW4064 administration most effects are mediated by the increased body weight gain we describe.…”

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

“…Bile acids are natural ligands for the nuclear receptor, farnesoid X receptor (FXR), and the plasma membranebound bile acid receptor TGR5 [also known as G protein-coupled bile acid receptor 1 (Gpbar1); membrane-type receptor for bile acids (M-BAR)]. Through activation of these receptors bile acids regulate lipid (9)(10)(11), glucose (12)(13)(14)(15)(16), and energy homeostasis (17) in addition to regulating their own synthesis (18), conjugation (19), transport (20)(21)(22), and detoxification (19,23,24). The global signaling capacity of bile acids is currently unclear; however, the expression of bile acid receptors FXR and TGR5 in tissues outside of the enterohepatic circulation, including the kidney (25) and heart (26,27), suggests a greater role throughout the body.…”

Nuevos receptores nucleares heterodiméricos: reguladores metabólicos con impacto en fisiopatología y su proyección terapéutica en dislipidemias y diabetes mellitus

“…Adicionalmente, la activación de FXR incrementa la expresión hepática de la enzima fosfoenolpiruvato carboxiquinasa, que cataliza la etapa limitante de la neoglucogénesis. Este resultado concuerda con una mayor secreción de glucosa en hepatocitos en cultivo tratados con agonistas naturales y sintéticos de FXR 52 , por lo que la activación de este receptor podría, hipotéti-camente, conducir a un estado hiperglicémico. Más aún, la activación de FXR podría estimular la glicogenólisis y, por lo tanto, incrementar por esta otra vía la generación hepática de glucosa 52 .…”

“…Este resultado concuerda con una mayor secreción de glucosa en hepatocitos en cultivo tratados con agonistas naturales y sintéticos de FXR 52 , por lo que la activación de este receptor podría, hipotéti-camente, conducir a un estado hiperglicémico. Más aún, la activación de FXR podría estimular la glicogenólisis y, por lo tanto, incrementar por esta otra vía la generación hepática de glucosa 52 . Concordante con estos antecedentes, el ratón deficiente de FXR exhibe una mayor tolerancia a la glucosa y una sensibilidad aumentada a la insulina 52 , lo cual reafirma que la inhibición terapéutica de FXR debiera ser beneficiosa para el metabolismo de los glúcidos en condiciones de resistencia insulínica.…”

“…Más aún, la activación de FXR podría estimular la glicogenólisis y, por lo tanto, incrementar por esta otra vía la generación hepática de glucosa 52 . Concordante con estos antecedentes, el ratón deficiente de FXR exhibe una mayor tolerancia a la glucosa y una sensibilidad aumentada a la insulina 52 , lo cual reafirma que la inhibición terapéutica de FXR debiera ser beneficiosa para el metabolismo de los glúcidos en condiciones de resistencia insulínica.…”