title: Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.
abstract: 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.
authors.affiliation: Cell and Molecular Biology Laboratory, Department of Biology, San Diego State University, San Diego, CA 92182, USA. rdavis@sciences.sdsu.edu
authors.forename: Roger A
authors.initials: RA
authors.lastname: Davis
authors.forename: Jon H
authors.initials: JH
authors.lastname: Miyake
authors.forename: To Yuen
authors.initials: TY
authors.lastname: Hui
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
mesh_terms: 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
chemical_list: 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