Bile acids are crucial for lipid homeostasis in the liver. During the last decade, researchers have discovered that bile acids not only act as detergents, but also as important signaling molecules. They have been shown to regulate the expression of numerous genes encoding enzymes/proteins involved in the metabolism/synthesis of bile acids, glucose, fatty acids, and lipoproteins as well as energy metabolism by activating specific nuclear receptors, a G protein coupled receptor (GPCR, TGR5), and multiple signaling pathways in cells of the liver and gastrointestinal tract. We have previously reported that conjugated bile acids activate the AKT and ERK1/2 pathways via G?i protein coupled receptor(s). Our most recent studies show that bile acids upregulate sphingosine kinase 2 (SphK2) expression (at both mRNA and protein levels) and enzyme activity and increase serum sphingosine-1-phosphate (S1P) levels. Activation of SphK2 by ERK1/2 increases nuclear S1P levels, which has been shown to be an inhibitor of specific histone deacetylases (HDAC 1 and 2). Increased histone acetylation is often associated with an increase in the transcriptional activity of physiologically linked genes. Our preliminary data strongly indicates that conjugated bile acids along with S1P activate the S1P receptor 2 (S1P2), which further activates the downstream ERK1/2 and AKT signaling pathways in hepatocytes. We recently discovered that in SphK2-/- mice the mRNA levels of key transcriptional factors and key enzymes involved in hepatic lipid metabolism were significantly down-regulated. The SphK2-/- mouse was also found to have an ~18-fold increase in serum triglycerides and a 2 to 5-fold decrease in both HDL and LDL as compared to wild-type control mice. Moreover, tauroursodeoxycholate (TUDCA)-mediated inhibition of lipid accumulation was reversed in the primary hepatocytes of S1P2-/- and SphK2-/- mice. However, the physiological link between bile acids, S1P, S1P receptors and their roles in regulating hepatic sterol/lipid metabolism have not been revealed. Based on the recent studies and our preliminary results, we hypothesize that bile acid-mediated activation of S1P2 plays a critical role in regulating hepatic lipid metabolism by phosphorylation and activation of SphK2 in the nucleus. The following three specific aims are proposed to test our central hypothesis.
Aim 1 : Characterize the activation of S1P2 by different bile acids and determine the structural-functional relationship of S1P2 and bile acids;
Aim 2 : Elucidate the role of S1P2 and SphK2 in bile acid-mediated regulation of hepatic sterol/lipid metabolism using S1P2-/- and SphK2-/- mice models;
Aim 3 : Determine the effects of administration of different bile acids (TUDCA, glycocholate and deoxycholate) and S1P2 antagonist on SphK2 expression and activity as well as activities of HDAC1 and HDAC2 in the liver using an in vivo rat model of bile acid depletion. Completion of this study will not only establish a novel theory in bile acid biology, but will also provide new mechanistic insights into the pathophysiology of dyslipidemia and other metabolic diseases including non-alcoholic fatty liver disease (NAFLD). Also, this study has potential impact on the identification and development of novel therapeutic targets for effective treatment of NAFLD and other related metabolic diseases.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and dysregulation of lipid metabolism represents an important pathological factor of NAFLD. Bile acids and sphingosine 1-phosphate (S1P) are important regulators of lipid homeostasis in the liver, however, the physiological link between bile acids, S1P, S1P receptors and their roles in regulating hepatic sterol/lipid metabolism have not been revealed. A complete understanding of bile acid and S1P biology will provide new approaches for effective treatment of NAFLD and other related metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057543-13
Application #
8637977
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2000-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$325,163
Indirect Cost
$107,663
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Nagahashi, Masayuki; Takabe, Kazuaki; Liu, Runping et al. (2015) Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology 61:1216-26
Zhou, Huiping; Hylemon, Phillip B (2014) Bile acids are nutrient signaling hormones. Steroids 86:62-8
Cazanave, S C; Wang, X; Zhou, H et al. (2014) Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis. Cell Death Differ 21:1303-12
Liu, Runping; Zhao, Renping; Zhou, Xiqiao et al. (2014) Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60:908-18
Wu, Xudong; Li, Yunzhou; Peng, Kesong et al. (2014) HIV protease inhibitors in gut barrier dysfunction and liver injury. Curr Opin Pharmacol 19:61-6
Zhang, Xiaoxuan; Wang, Guangji; Gurley, Emily C et al. (2014) Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLoS One 9:e107072
Studer, Elaine; Zhou, Xiqiao; Zhao, Renping et al. (2012) Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology 55:267-76
Cao, Risheng; Cronk, Zhumei Xu; Zha, Weibin et al. (2010) Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway. J Lipid Res 51:2234-44
Hylemon, Phillip B; Zhou, Huiping; Pandak, William M et al. (2009) Bile acids as regulatory molecules. J Lipid Res 50:1509-20
Kang, Dae-Joong; Ridlon, Jason M; Moore 2nd, Doyle Ray et al. (2008) Clostridium scindens baiCD and baiH genes encode stereo-specific 7alpha/7beta-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductases. Biochim Biophys Acta 1781:16-25

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