Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia.
Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.
Zhang
Yanqiao
Y
Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, USA. yzhang@neoucom.edu
Yin
Liya
L
Anderson
Jody
J
Ma
Huiyan
H
Gonzalez
Frank J
FJ
Willson
Timothy M
TM
Edwards
Peter A
PA
D000042:Absorption; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003327:Coronary Disease / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002784:Cholesterol; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D008074:Lipoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D000099150:Receptor, Farnesoid X-Activated; C496593:Hnf4a protein, mouse; C454739:Scarb1 protein, mouse