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Nuclear receptors, bile-acid detoxification, and cholestasis

Faculty of Science, Technology and Engineering, La Trobe University, Melbourne, Victoria, Australia
The Lancet (Impact Factor: 45.22). 03/2006; 367(9509):454-6. DOI: 10.1016/S0140-6736(06)68156-7
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    • "References Bile acid absorption Decreased Conversion of cholesterol into bile acids is Ellegard and Andersson 2007 increased and blood cholesterol level is decreased CYP7A1 Increased Conversion of cholesterol into bile acids is increased Ellegard and Andersson 2007 LDLR Increased Cholesterol transport into hepatocytes is increased Watkins 2004 CYP3A4 Not known CYP3A4 increased bile acid metabolism Chen and Raymond 2006 HMG CoA reductase Increased Cholesterol synthesis is increased Ellegard and Andersson 2007 Cholesterol absorption Decreased Blood level of cholesterol is decreased Ellegard and Andersson 2007, and Watkins 2004 on the absorption of glucose (Wood and others 1994). Due to a decrease in bile acid content in the small intestine, emulsification of fats is decreased, which in addition to the viscosity effects mentioned reduces fat absorption. "
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    ABSTRACT: This article presents an overview of the recent advances into the health promoting potentials of oat β‐glucan. Oat β‐glucan (OβG) consists mainly of the linear polysaccharide (1→3), (1→4)‐β‐D‐glucan and is often called β‐glucan. This soluble oat fiber is able to attenuate blood postprandial glycemic and insulinemic responses, to lower blood total cholesterol and low‐density lipoprotein (LDL) cholesterol, and to improve high‐density lipoprotein (HDL) cholesterol and blood lipid profiles as well as to maintain body weight. Thus, OβG intake is beneficial in the prevention, treatment, and control of diabetes and cardiovascular diseases. In addition, OβG can stimulate immune functions by activating monocytes/macrophages and increasing the amounts of immunoglobulin, NK cells, killer T‐cells, and so on, which will improve resistance to cancer and infectious and parasitic diseases, as well as increase biological therapies and their prevention. All these health benefits of OβG may be explained by its physicochemical properties (such as viscosity, molecular weight) which can be affected by extraction methods and its behavior in gastrointestinal tract. Articles documenting these health benefits and effects are reviewed.
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    • "A single dose of 5 mg CD/kg to C57BL/6 mice also significantly alters tissue distribution of exogenous [ 14 C]CD or [ 14 C]CH, decreasing hepatic disposition and increasing distribution to other tissues (Carpenter and Curtis 1991). CH is an important constituent of cell membranes and a precursor of steroid hormones and bile acids (Chen and Raymond 2006; Tabas 2002). However accumulation of excess CH contributes to several diseases especially heart attacks and stroke by promoting atherosclerosis (Krieger 1999). "
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    ABSTRACT: Organochlorine (OC) insecticides continue to occur in tissues of humans and wildlife throughout the world although they were banned in the United States a few decades ago. Low doses of the OC insecticide chlordecone (CD) alter hepatic disposition of lipophilic xenobiotics and perturb lipid homeostasis in rainbow trout, mice and rats. CD pretreatment altered tissue and hepatic subcellular distribution of exogenous [(14)C]cholesterol (CH) equivalents 4 and 16 h after a bolus intraperitoneal (ip) injection of 5 ml corn oil/kg that contained 10 mg CH/kg. CD pretreatment altered tissue distribution of exogenously administered [(14)C]CH by decreased hepatic and renal accumulation, and increased biliary excretion up to 300%. Biliary excretion of polar [(14)C]CH metabolites was not altered by CD. CD pretreatment decreased subcellular distribution of [(14)C]CH equivalents in hepatic cytosol and microsomes and lipoprotein-rich fraction-to-homogenate ratio. CD pretreatment increased the ratio of [(14)C]CH equivalents in high density lipoprotein (HDL) to that in plasma and reduced [(14)C]CH equivalents in the non-HDL fraction 4 h after a bolus lipid dose. CD pretreatment increased plasma non-HDL total CH by 80% 4 h after a bolus lipid dose. Scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G8 (ABCG8) proteins were quantified by western blotting in hepatic membranes from control and CD treated mice. Liver membrane contents of SR-BI and ABCG8 proteins were unchanged by CD pretreatment. The data demonstrated that a single dose of CD altered CH homeostasis and lipoprotein metabolism.
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    ABSTRACT: Bile acids play important functions in the maintenance of bile acid homeostasis. However, due to their detergent properties, these acids are inherently cytotoxic and their accumulation in liver is associated with hepatic disorders such as cholestasis. During their enterohepatic circulation, bile acids undergo several metabolic alterations, including amidation, hydroxylation, sulfonation, and glucuronidation. Most of these transformations facilitate the excretion of bile acids into the bile (amidation and sulfonation) or into the blood for subsequent urinary elimination (hydroxylation, sulfonation, and glucuronidation). In this review, the role of various nuclear receptors and transcription factors in the expression of bile acid detoxification enzymes is summarized. In particular, the coordinate manner in which the xenobiotic sensors pregnane X receptor and constitutive androstane receptor, the lipid sensors liver X receptor, farnesoid X receptor, peroxisome proliferator-activated receptor alpha, and vitamin D receptor, and the orphan receptors hepatocyte nuclear factor 4alpha and small heterodimer partner regulate bile acid detoxification is detailed. Finally, we conclude by discussing the importance of these transcription factors as promising drug targets for the correction of cholestasis.
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