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      A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

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      Publication date:
      Journal: Molecular Cell
      Keywords: Animals, Bile Acids and Salts, biosynthesis, Blotting, Northern, Cells, Cultured, Cholesterol 7-alpha-Hydroxylase, genetics, metabolism, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, physiology, Hepatocytes, cytology, enzymology, Humans, Intracellular Signaling Peptides and Proteins, Male, Promoter Regions, Genetic, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Messenger, analysis, Rats, Rats, Inbred F344, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Transcription Factors, Transfection

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          Abstract

          Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

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          • Record: found
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          Identification of a nuclear receptor for bile acids.

          M. Makishima, A. Okamoto, J Repa … (1999)
          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
          Article 0 comments Cited 562 times – based on 0 reviews     Review now
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            Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.

            Christopher J Sinal, Masahiro Tohkin, Masaaki Miyata … (2000)
            Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
            Article 0 comments Cited 371 times – based on 0 reviews     Review now
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              Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

              H. Wang, J. Chen, K Hollister … (1999)
              The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
              Article 0 comments Cited 335 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 11030332

                ScienceOpen disciplines: Chemistry
                Keywords: Animals,Bile Acids and Salts,biosynthesis,Blotting, Northern,Cells, Cultured,Cholesterol 7-alpha-Hydroxylase,genetics,metabolism,DNA-Binding Proteins,Gene Expression Regulation, Enzymologic,physiology,Hepatocytes,cytology,enzymology,Humans,Intracellular Signaling Peptides and Proteins,Male,Promoter Regions, Genetic,Protein Tyrosine Phosphatase, Non-Receptor Type 11,Protein Tyrosine Phosphatase, Non-Receptor Type 6,Protein Tyrosine Phosphatases,RNA, Messenger,analysis,Rats,Rats, Inbred F344,Receptors, Cytoplasmic and Nuclear,Repressor Proteins,Transcription Factors,Transfection
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                ScienceOpen disciplines: Chemistry
                Keywords: Animals, Bile Acids and Salts, biosynthesis, Blotting, Northern, Cells, Cultured, Cholesterol 7-alpha-Hydroxylase, genetics, metabolism, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, physiology, Hepatocytes, cytology, enzymology, Humans, Intracellular Signaling Peptides and Proteins, Male, Promoter Regions, Genetic, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Messenger, analysis, Rats, Rats, Inbred F344, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Transcription Factors, Transfection

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