The Entero-Hepatic Nuclear Receptors Integrate Cholesterol, Lipid, and Bile Acid Homeostasis

Cholesterol and bile acid metabolism is tightly controlled by nuclear receptors. The liver X receptor (LXR), an oxysterol-activated nuclear receptor, limits cholesterol accumulation in the body. LXR achieves this effect : 1) by enhancing reverse cholesterol transport to the liver : 2) by the stimulation of cholesterol excretion through its conversion to bile acids : and 3) by the inhibition of intestinal cholesterol absorption. Whereas LXR is a master controller of cholesterol metabolism, the farnesol X receptor (FXR), a bile acid-activated receptor, coordinates bile acid homeostasis. FXR stimulates the re-uptake of bile acids from the intestine via a process termed entero-hepatic circulation. Activated FXR also protects the liver against the toxic effects of excessive bile acid concentrations, through an indirect mechanism. In fact, FXR induces the small heterodimer partner (SHP), an atypical nuclear receptor, that attenuates further bile acid synthesis and bile acid import into the liver by inhibiting the action of nuclear receptors, such as the liver receptor homolog-1, the hepatic nuclear factor 4α, and the retinoid X receptor RXR). Finally, steroid and xenobiotic receptor / pregnane X receptor (SXR / PXR) exerts a hepatoprotective function by favoring the catabolism of toxic compounds such as secondary bile acids and xenobiotics. The complexity of these nuclear receptor-controlled regulatory circuits is only being recognized and further study is definitively required to understand the cross-regulation between these nuclear receptors and other transcription factors.