Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist.
The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.
Division of Nutritional Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Kyosuke
K
Fujita
Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
Yusuke
Y
Iguchi
Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
Mizuho
M
Une
Division of Nutritional Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. shirowat@inm.u-toyama.ac.jp.
Shiro
S
Watanabe
D000818:Animals; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D002793:Cholic Acids; D003840:Deoxycholic Acid / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D002793:Cholic Acids; D003840:Deoxycholic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C497388:Srebf1 protein, mouse; C004821:muricholic acid
Cholesterol ester; Fatty acid; Sterol regulatory element-binding protein 1c; Triglyceride