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Post by Max on Jul 4, 2005 6:47:19 GMT -5
There are several case reports of gall-stone formation in association with (Ro)accutane exposure in human subjects [4 and more]. The long term effects on gall-stone formation are unknown.
Activation of the retinoid x receptor (RXR), in a similiar manner as of (Ro)accutane induced activation, is found to antagonize (inhibit) the transcription of the farnoid x receptor (FXR) [2 and more] which could increase the susceptibility to pathologies like gallstone disease in human subjects exposed to the toxin.
Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. FXR agonists (the opposite of (Ro)accutane) are suggested to be a possible remedy for gallstone disease due to FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation [1, 3 and more].
Retinoid X receptor (RXR) antagonism of the farnesoid X receptor (FXR)
RXR agonist LG100268 antagonizes induction of BSEP expression mediated by endogenous and synthetic FXR ligands, CDCA and GW4064, respectively. Moreover, this antagonism is a general feature of RXR agonists and is attributed to a decrease in binding of FXR/RXR heterodimers to the BSEP-FXRE coupled with the inability of RXR agonists to recruit coactivators to FXR/RXR. FXR/RXR is suggested to be a conditionally permissive heterodimer and is the first example of RXR ligand-mediated antagonism of FXR activity. Because FXR agonists lower triglyceride levels, suggesting a novel role for RXR-mediated antagonism of FXR activity in the development of hypertriglyceridemia observed with RXR agonists in rodents and humans [2].
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Post by Max on Jul 4, 2005 6:47:52 GMT -5
References:
[1] Juran BD, Lazaridis KN. Is the FXR the fix for cholesterol gallstone disease? (2005) Hepatology. Jul;42(1):218-21.
[2] Kassam A, Miao B, Young PR, Mukherjee R. Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding.
(2003) J Biol Chem. Mar 21;278(12):10028-32.
[3] Doggrell SA. Farnesoid X receptor agonism -- a new approach to the treatment of cholesterol gallstone disease. (2005) Expert Opin Investig Drugs. Apr;14(4):535-8.
[4] Aurousseau MH, Levacher S, Beneton C, Blaise M, Pourriat JL. [Transient dysfibrinogenemia and thrombocytopenia associated with recurrent acute pancreatitis in the course of isotretinoin therapy]
(1995) Rev Med Interne. 16(8):622-5.
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Post by Max on Jul 4, 2005 7:23:21 GMT -5
Genes Dev. 2004 Jan 15;18(2):157-69. Epub 2004 Jan 16. Related Articles, Links
Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR.
Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA.
Department of Biological Chemistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1alpha regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent and -independent pathways. PGC-1alpha increases FXR activity through two pathways: (1) it increases FXR mRNA levels by coactivation of PPARgamma and HNF4alpha to enhance FXR gene transcription; and (2) it interacts with the DNA-binding domain of FXR to enhance the transcription of FXR target genes. Ectopic expression of PGC-1alpha in murine primary hepatocytes reduces triglyceride secretion by a process that is dependent on the presence of FXR. Consistent with these in vitro studies, we demonstrate that fasting induces hepatic expression of PGC-1alpha and FXR and results in decreased plasma triglyceride levels in wild-type but not in FXR-null mice. Our data suggest that PGC-1alpha plays an important physiological role in maintaining energy homeostasis during fasting by decreasing triglyceride production/secretion while it increases fatty acid beta-oxidation to meet energy needs.
PMID: 14729567 [PubMed - indexed for MEDLINE]
Biochem Biophys Res Commun. 2005 Apr 1;329(1):391-6. Related Articles, Links
Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor.
Savkur RS, Bramlett KS, Michael LF, Burris TP.
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
The pyruvate dehydrogenase complex (PDC) functions as an important junction in intermediary metabolism by influencing the utilization of fat versus carbohydrate as a source of fuel. Activation of PDC is achieved by phosphatases, whereas, inactivation is catalyzed by pyruvate dehydrogenase kinases (PDKs). The expression of PDK4 is highly regulated by the glucocorticoid and peroxisome proliferator-activated receptors. We demonstrate that the farnesoid X receptor (FXR; NR1H4), which regulates a variety of genes involved in lipoprotein metabolism, also regulates the expression of PDK4. Treatment of rat hepatoma cells as well as human primary hepatocytes with FXR agonists stimulates the expression of PDK4 to levels comparable to those obtained with glucocorticoids. In addition, treatment of mice with an FXR agonist significantly increased hepatic PDK4 expression, while concomitantly decreasing plasma triglyceride levels. Thus, activation of FXR may suppress glycolysis and enhance oxidation of fatty acids via inactivation of the PDC by increasing PDK4 expression.
PMID: 15721319 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 4, 2005 12:53:44 GMT -5
Scand J Gastroenterol Suppl. 2004;(241):60-9. Related Articles, Links
Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.
vanBerge-Henegouwen GP, Venneman NG, Portincasa P, Kosters A, van Erpecum KJ, Groen AK.
Gastrointestinal Research Unit, Dept. of Gastroenterology, UMC Utrecht, The Netherlands. gbergehe@azu.nl
In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.
Publication Types:
Review
Review, Tutorial
PMID: 15696852 [PubMed - indexed for MEDLINE]
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Post by hgd on Sept 7, 2018 19:43:39 GMT -5
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