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      Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity

      research-article
      1 , 2 , 3 , 4 , 1 , 1 , 2 , 5 , 6 , 7 , 8 , 8 , 9 , 10 , * , , 1 , * ,
      Journal of Hepatology
      Elsevier
      BAs, bile acids, NAFLD, non-alcoholic fatty liver disease, UDCA, ursodeoxycholic acid, vWAT, visceral white adipose tissue, FXR, farnesoid X receptor, SCD, stearoyl-Coa desaturase, NASH, non-alcoholic steatohepatitis, TGs, triglycerides, FAs, fatty acides, CYP7A1, cholesterol 7α-hydroxylase, SHP, small heterodimer partner, FGF19, fibroblast growth factor 19, SREBP1c, sterol regulatory element-binding protein-1c, FASN, fatty acid synthase, VLDL, very low density lipoproteins, CDCA, chenodeoxycholic acid, CA, cholic acid, C4, 7α-hydroxy-4-cholesten-3-one, HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase, ABC, ATP-binding cassette, LDLR, low density lipoprotein receptor, MA, myristic acid, PA, palmitic acid, SA, stearic acid, OA, oleic acid, MTTP, microsomal triglyceride transfer protein, ApoB, apolipoprotein B, FATP1, fatty acid transport protein 1, nCEH, neutral cholesterol ester hydrolase, Non-alcoholic fatty liver disease, FGF19, 3-hydroxy-3-methylglutaryl-CoA reductase, Lipogenesis, Stearoyl-CoA desaturase

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          Graphical abstract

          Abstract

          Background & Aims

          Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients.

          Methods

          In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery.

          Results

          Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid.

          Conclusion

          These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT.

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          Most cited references24

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          Identification of a nuclear receptor for bile acids.

          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.
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            Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

            We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.
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              • Record: found
              • Abstract: found
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              Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.

              Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                J Hepatol
                J. Hepatol
                Journal of Hepatology
                Elsevier
                0168-8278
                1600-0641
                1 June 2015
                June 2015
                : 62
                : 6
                : 1398-1404
                Affiliations
                [1 ]Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
                [2 ]Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, Graz, Austria
                [3 ]Karolinska Institutet, Department of Clinical Science at Danderyds Hospital, Stockholm, Sweden
                [4 ]Department of Surgery, Ersta Hospital, Stockholm, Sweden
                [5 ]Core Facility for Mass Spectrometry, Medical University of Graz, Graz, Austria
                [6 ]Institute of Pathology, Medical University of Graz, Graz, Austria
                [7 ]Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
                [8 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
                [9 ]Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
                [10 ]Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
                Author notes
                [* ]Corresponding authors. Addresses: Professor of Clinical Hepatology, Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, S-41345 Gothenburg, Sweden. Tel.: +46 70 8774073; fax: +46 31 827458 (H.-U. Marschall) or Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40 40047410; fax: +43 1 40 400 47350 (M. Trauner). hanns-ulrich.marschall@ 123456gu.se michael.trauner@ 123456meduniwien.ac.at
                [†]

                Shared senior authorship and correspondence.

                Article
                S0168-8278(15)00010-0
                10.1016/j.jhep.2014.12.034
                4451470
                25617503
                5f6dbd30-1a8e-4ee3-b104-74656f1dcf70
                © 2015 European Association for the Study of the Liver. Elsevier B.V. All rights reserved.
                History
                : 3 November 2014
                : 17 December 2014
                : 22 December 2014
                Categories
                Research Article

                Gastroenterology & Hepatology
                bas, bile acids,nafld, non-alcoholic fatty liver disease,udca, ursodeoxycholic acid,vwat, visceral white adipose tissue,fxr, farnesoid x receptor,scd, stearoyl-coa desaturase,nash, non-alcoholic steatohepatitis,tgs, triglycerides,fas, fatty acides,cyp7a1, cholesterol 7α-hydroxylase,shp, small heterodimer partner,fgf19, fibroblast growth factor 19,srebp1c, sterol regulatory element-binding protein-1c,fasn, fatty acid synthase,vldl, very low density lipoproteins,cdca, chenodeoxycholic acid,ca, cholic acid,c4, 7α-hydroxy-4-cholesten-3-one,hmgcr, 3-hydroxy-3-methylglutaryl-coa reductase,abc, atp-binding cassette,ldlr, low density lipoprotein receptor,ma, myristic acid,pa, palmitic acid,sa, stearic acid,oa, oleic acid,mttp, microsomal triglyceride transfer protein,apob, apolipoprotein b,fatp1, fatty acid transport protein 1,nceh, neutral cholesterol ester hydrolase,non-alcoholic fatty liver disease,fgf19,3-hydroxy-3-methylglutaryl-coa reductase,lipogenesis,stearoyl-coa desaturase

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