Redundant pathways for negative feedback regulation of bile acid production.
The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.
Wang
Li
L
Department of Molecular and Cellular Biology, Houston, TX 77030, USA.
Lee
Yoon-Kwang
YK
Bundman
Donnie
D
Han
Yunqing
Y
Thevananther
Sundararajah
S
Kim
Chang Soo
CS
Chua
Steven S
SS
Wei
Ping
P
Heyman
Richard A
RA
Karin
Michael
M
Moore
David D
DD
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000378:metabolism; D005246:Feedback / Q000502:physiology*; D006706:Homeostasis; D007555:Isoxazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D047488:Retinoid X Receptors; D013234:Stem Cells / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009539:Nicotinic Acids; D009687:Nuclear Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C412815:GW 4064; C095104:LG 100268