title: Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression.
abstract: Bile acids are important hormones during the feed/fast cycle, allowing the liver to coordinately regulate nutrient metabolism. How they accomplish this has not been fully elucidated. Conjugated bile acids activate both the ERK1/2 and AKT signaling pathways via sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes and in vivo. Here, we report that feeding mice a high-fat diet, infusion of taurocholate into the chronic bile fistula rat, or overexpression of the gene encoding S1PR2 in mouse hepatocytes significantly upregulated hepatic sphingosine kinase 2 (SphK2) but not SphK1. Key genes encoding nuclear receptors/enzymes involved in nutrient metabolism were significantly downregulated in livers of S1PR2(-/-) and SphK2(-/-) mice. In contrast, overexpression of the gene encoding S1PR2 in primary mouse hepatocytes differentially increased SphK2, but not SphK1, and mRNA levels of key genes involved in nutrient metabolism. Nuclear levels of sphingosine-1-phosphate, an endogenous inhibitor of histone deacetylases 1 and 2, as well as the acetylation of histones H3K9, H4K5, and H2BK12 were significantly decreased in hepatocytes prepared from S1PR2(-/-) and SphK2(-/-) mice.
  
  
  CONCLUSIONS
  Both S1PR2(-/-) and SphK2(-/-) mice rapidly developed fatty livers on a high-fat diet, suggesting the importance of conjugated bile acids, S1PR2, and SphK2 in regulating hepatic lipid metabolism.
authors.affiliation: Department of Surgery, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA; Department of Biochemistry and Molecular Biology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.forename: Kesong
authors.initials: K
authors.lastname: Peng
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D005786:Gene Expression Regulation; D022781:Hepatocytes; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000502:physiology*; D000099157:Sphingosine Kinase
chemical_list: D001647:Bile Acids and Salts; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase