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

التفاصيل البيبلوغرافية
العنوان: Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity
المؤلفون: Michael Trauner, Hanns-Ulrich Marschall, Curt Einarsson, Anders Thorell, Tatjana Stojakovic, Pooja Jha, Guenter Fauler, Thierry Claudel, Bastian Hoesel, Michaela Mueller, Harald Koefeler, Carolin Lackner
المصدر: Journal of Hepatology
بيانات النشر: European Association for the Study of the Liver. Published by Elsevier B.V.
مصطلحات موضوعية: vWAT, visceral white adipose tissue, C4, 7α-hydroxy-4-cholesten-3-one, FASN, fatty acid synthase, Receptors, Cytoplasmic and Nuclear, FGF19, SHP, small heterodimer partner, LDLR, low density lipoprotein receptor, chemistry.chemical_compound, SA, stearic acid, CA, cholic acid, TGs, triglycerides, Bile acid, Chemistry, ABC, ATP-binding cassette, MTTP, microsomal triglyceride transfer protein, Ursodeoxycholic Acid, FGF19, fibroblast growth factor 19, Ursodeoxycholic acid, Obesity, Morbid, 3. Good health, Stearoyl-CoA desaturase, HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase, lipids (amino acids, peptides, and proteins), Research Article, medicine.drug, NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, MA, myristic acid, FAs, fatty acides, medicine.drug_class, NASH, non-alcoholic steatohepatitis, Cholesterol 7 alpha-hydroxylase, UDCA, ursodeoxycholic acid, CDCA, chenodeoxycholic acid, Bile Acids and Salts, PA, palmitic acid, FXR, farnesoid X receptor, nCEH, neutral cholesterol ester hydrolase, Internal medicine, 7α-Hydroxy-4-cholesten-3-one, medicine, Humans, ApoB, apolipoprotein B, SREBP1c, sterol regulatory element-binding protein-1c, Liver X receptor, ComputingMethodologies_COMPUTERGRAPHICS, VLDL, very low density lipoproteins, Hepatology, BAs, bile acids, Lipogenesis, OA, oleic acid, Lipid metabolism, CYP7A1, cholesterol 7α-hydroxylase, Lipid Metabolism, FATP1, fatty acid transport protein 1, Endocrinology, 3-hydroxy-3-methylglutaryl-CoA reductase, Farnesoid X receptor, SCD, stearoyl-Coa desaturase, Non-alcoholic fatty liver disease
الوصف: Graphical 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.
اللغة: English
تدمد: 0168-8278
DOI: 10.1016/j.jhep.2014.12.034
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd82151b619f124808fea36eb0c8125dTest
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....cd82151b619f124808fea36eb0c8125d
قاعدة البيانات: OpenAIRE
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Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22vWAT%2C+visceral+white+adipose+tissue%22">vWAT, visceral white adipose tissue</searchLink><br /><searchLink fieldCode="DE" term="%22C4%2C+7α-hydroxy-4-cholesten-3-one%22">C4, 7α-hydroxy-4-cholesten-3-one</searchLink><br /><searchLink fieldCode="DE" term="%22FASN%2C+fatty+acid+synthase%22">FASN, fatty acid synthase</searchLink><br /><searchLink fieldCode="DE" term="%22Receptors%2C+Cytoplasmic+and+Nuclear%22">Receptors, Cytoplasmic and Nuclear</searchLink><br /><searchLink fieldCode="DE" term="%22FGF19%22">FGF19</searchLink><br /><searchLink fieldCode="DE" term="%22SHP%2C+small+heterodimer+partner%22">SHP, small heterodimer partner</searchLink><br /><searchLink fieldCode="DE" term="%22LDLR%2C+low+density+lipoprotein+receptor%22">LDLR, low density lipoprotein receptor</searchLink><br /><searchLink fieldCode="DE" term="%22chemistry%2Echemical%5Fcompound%22">chemistry.chemical_compound</searchLink><br /><searchLink fieldCode="DE" term="%22SA%2C+stearic+acid%22">SA, stearic acid</searchLink><br /><searchLink fieldCode="DE" term="%22CA%2C+cholic+acid%22">CA, cholic acid</searchLink><br /><searchLink fieldCode="DE" term="%22TGs%2C+triglycerides%22">TGs, triglycerides</searchLink><br /><searchLink fieldCode="DE" term="%22Bile+acid%22">Bile acid</searchLink><br /><searchLink fieldCode="DE" term="%22Chemistry%22">Chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22ABC%2C+ATP-binding+cassette%22">ABC, ATP-binding cassette</searchLink><br /><searchLink fieldCode="DE" term="%22MTTP%2C+microsomal+triglyceride+transfer+protein%22">MTTP, microsomal triglyceride transfer protein</searchLink><br /><searchLink fieldCode="DE" term="%22Ursodeoxycholic+Acid%22">Ursodeoxycholic Acid</searchLink><br /><searchLink fieldCode="DE" term="%22FGF19%2C+fibroblast+growth+factor+19%22">FGF19, fibroblast growth factor 19</searchLink><br /><searchLink fieldCode="DE" term="%22Ursodeoxycholic+acid%22">Ursodeoxycholic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Obesity%2C+Morbid%22">Obesity, Morbid</searchLink><br /><searchLink fieldCode="DE" term="%223%2E+Good+health%22">3. Good health</searchLink><br /><searchLink fieldCode="DE" term="%22Stearoyl-CoA+desaturase%22">Stearoyl-CoA desaturase</searchLink><br /><searchLink fieldCode="DE" term="%22HMGCR%2C+3-hydroxy-3-methylglutaryl-CoA+reductase%22">HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase</searchLink><br /><searchLink fieldCode="DE" term="%22lipids+%28amino+acids%2C+peptides%2C+and+proteins%29%22">lipids (amino acids, peptides, and proteins)</searchLink><br /><searchLink fieldCode="DE" term="%22Research+Article%22">Research Article</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edrug%22">medicine.drug</searchLink><br /><searchLink fieldCode="DE" term="%22NAFLD%2C+non-alcoholic+fatty+liver+disease%22">NAFLD, non-alcoholic fatty liver disease</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Emedical%5Fspecialty%22">medicine.medical_specialty</searchLink><br /><searchLink fieldCode="DE" term="%22MA%2C+myristic+acid%22">MA, myristic acid</searchLink><br /><searchLink fieldCode="DE" term="%22FAs%2C+fatty+acides%22">FAs, fatty acides</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edrug%5Fclass%22">medicine.drug_class</searchLink><br /><searchLink fieldCode="DE" term="%22NASH%2C+non-alcoholic+steatohepatitis%22">NASH, non-alcoholic steatohepatitis</searchLink><br /><searchLink fieldCode="DE" term="%22Cholesterol+7+alpha-hydroxylase%22">Cholesterol 7 alpha-hydroxylase</searchLink><br /><searchLink fieldCode="DE" term="%22UDCA%2C+ursodeoxycholic+acid%22">UDCA, ursodeoxycholic acid</searchLink><br /><searchLink fieldCode="DE" term="%22CDCA%2C+chenodeoxycholic+acid%22">CDCA, chenodeoxycholic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Bile+Acids+and+Salts%22">Bile Acids and Salts</searchLink><br /><searchLink fieldCode="DE" term="%22PA%2C+palmitic+acid%22">PA, palmitic acid</searchLink><br /><searchLink fieldCode="DE" term="%22FXR%2C+farnesoid+X+receptor%22">FXR, farnesoid X receptor</searchLink><br /><searchLink fieldCode="DE" term="%22nCEH%2C+neutral+cholesterol+ester+hydrolase%22">nCEH, neutral cholesterol ester hydrolase</searchLink><br /><searchLink fieldCode="DE" term="%22Internal+medicine%22">Internal medicine</searchLink><br /><searchLink fieldCode="DE" term="%227α-Hydroxy-4-cholesten-3-one%22">7α-Hydroxy-4-cholesten-3-one</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%22">medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Humans%22">Humans</searchLink><br /><searchLink fieldCode="DE" term="%22ApoB%2C+apolipoprotein+B%22">ApoB, apolipoprotein B</searchLink><br /><searchLink fieldCode="DE" term="%22SREBP1c%2C+sterol+regulatory+element-binding+protein-1c%22">SREBP1c, sterol regulatory element-binding protein-1c</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+X+receptor%22">Liver X receptor</searchLink><br /><searchLink fieldCode="DE" term="%22ComputingMethodologies%5FCOMPUTERGRAPHICS%22">ComputingMethodologies_COMPUTERGRAPHICS</searchLink><br /><searchLink fieldCode="DE" term="%22VLDL%2C+very+low+density+lipoproteins%22">VLDL, very low density lipoproteins</searchLink><br /><searchLink fieldCode="DE" term="%22Hepatology%22">Hepatology</searchLink><br /><searchLink fieldCode="DE" term="%22BAs%2C+bile+acids%22">BAs, bile acids</searchLink><br /><searchLink fieldCode="DE" term="%22Lipogenesis%22">Lipogenesis</searchLink><br /><searchLink fieldCode="DE" term="%22OA%2C+oleic+acid%22">OA, oleic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Lipid+metabolism%22">Lipid metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22CYP7A1%2C+cholesterol+7α-hydroxylase%22">CYP7A1, cholesterol 7α-hydroxylase</searchLink><br /><searchLink fieldCode="DE" term="%22Lipid+Metabolism%22">Lipid Metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22FATP1%2C+fatty+acid+transport+protein+1%22">FATP1, fatty acid transport protein 1</searchLink><br /><searchLink fieldCode="DE" term="%22Endocrinology%22">Endocrinology</searchLink><br /><searchLink fieldCode="DE" term="%223-hydroxy-3-methylglutaryl-CoA+reductase%22">3-hydroxy-3-methylglutaryl-CoA reductase</searchLink><br /><searchLink fieldCode="DE" term="%22Farnesoid+X+receptor%22">Farnesoid X receptor</searchLink><br /><searchLink fieldCode="DE" term="%22SCD%2C+stearoyl-Coa+desaturase%22">SCD, stearoyl-Coa desaturase</searchLink><br /><searchLink fieldCode="DE" term="%22Non-alcoholic+fatty+liver+disease%22">Non-alcoholic fatty liver disease</searchLink> )
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