Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.
Cholesterol-7alpha-hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tissues. The discovery of farnesoid X receptor (FXR), the nuclear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid activation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcription of CYP7A1. Recent studies show there is an "FXR/SHP-independent" mechanism that also represses CYP7A1 expression. This "FXR/SHP-independent" pathway involves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and secretion of cytokines. These inflammatory cytokines, which include tumor necrosis factor alpha and interleukin-1beta, act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene.
Davis
Roger A
RA
Cell and Molecular Biology Laboratory, Department of Biology, San Diego State University, San Diego, CA 92182, USA. rdavis@sciences.sdsu.edu
Miyake
Jon H
JH
Hui
To Yuen
TY
Spann
Nathanael J
NJ
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism / Q000494:pharmacology; D002940:Circadian Rhythm; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003902:Detergents / Q000737:chemistry / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012323:RNA Processing, Post-Transcriptional; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D016207:Cytokines; D004268:DNA-Binding Proteins; D003902:Detergents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated