Preferred Label : Regulation of Cholesterol Metabolism Pathway;
NCIt related terms : FXR and LXR Regulation of Cholesterol Metabolism;
Alternative definition : BIOCARTA: Cholesterol is essential for life but a key in the development of heart
disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake,
cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile
acids. Inhibition of cholesterol biosynthesis up regulates LDLR expression and is
the mechanism of action of many drugs used to lower plasma LDL to reduce coronary
heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear
receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers
with the retinoic acid RXR receptors and that are activated by cholesterol metabolites.
One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol
biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from
the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some
of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through
LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the
rate-limiting step in bile acid biosynthesis and a major route for the elimination
of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver.
In the intestine LXR activates the ABC-1 gene, a transporter that actively transports
cholesterol out of cells to clear it from the body. Activation of ABC-1 expression
by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by
which LXR plays a role in heart disease. The FXR receptor is activated by bile acids.
In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback
inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine,
FXR activates expression of I-BABP, a protein that increases the transport of bile
acids back to the liver from the intestine, reducing their excretion. Drugs targeting
the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis
and heart disease in the future. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_fxrPathway;
Origin ID : C39085;
UMLS CUI : C1514824;
- Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element