The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling

Fang, Sungsoon

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https://hdl.handle.net/2142/47090 Copy

Description

Title

The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling

Author(s)

Fang, Sungsoon

Issue Date

2008

Director of Research (if dissertation) or Advisor (if thesis)

Kemper, Byron W.

Doctoral Committee Chair(s)

Kemper, Jongsook K.

Committee Member(s)

• Katzenellenbogen, Benita S.
• Nardulli, Ann M.
• Bagchi, Milan K.
• Mizzen, Craig A.

Department of Study

Molecular & Integrative Physiology

Discipline

Molecular & Integrative Physiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Bile acids
• Bile acid signaling
• Farnesoid X receptor (FXR)
• Small heterodimer partner (SHP)

Language

en

Abstract

Bile acids, the end-product of cholesterol catabolism, are important for absorption and solubilization of lipids in the intestine because of their detergent properties. In addition to their roles as detergents, previous studies have revealed that bile acids function as signaling molecules in metabolic pathways such as glucose and fatty acid metabolism as well as cholesterol/bile acid homeostasis. Furthermore, many reports have shown that bile acid signaling finely regulates numerous metabolically relevant genes at the level of their transcription. However, the molecular mechanisms of bile acid signaling to control transcription of genes are poorly understood. In recent years, two orphan nuclear receptors, farnesoid X receptor (FXR) and small heterodimer partner (SHP), have been identified as key regulators in bile acid signaling. FXR was revealed as the first in vivo bile acid biosensor and was shown to regulate cholesterol/bile acid homeostasis by suppressing the transcription of cholesterol 7-a hydroxylase (CYP7A1), the first and rate-limiting enzyme in bile acid biosynthesis. The discovery of the bile acid receptor FXR provided a better understanding of the potential roles of orphan nuclear receptors in transcriptional regulation by bile acids. Consecutive reports showed that bile acid-activated FXR suppressed CYP7A1 gene transcription by inducing another orphan nuclear receptor, small heterodimer partner (SHP), that plays a key role in the negative feedback regulation of bile acid synthesis. Later then, our group showed that bile acid-induced SHP actively recruits the mSin3A/HDAC corepressors and the Swi/SNF chromatin remodeling complex, containing Brm as a central ATPase, to the promoter and suppresses the transcription of the CYP7A1 gene. In order to delineate the repression mechanism of CYP7A1 mediated by SHP, I examined whether histone modifications are also involved in CYP7A1 repression by SHP and whether a functional interplay between chromatin modifying enzymes occurs during the repression of the CYP7A1 gene. Recently, I reported that histone methyltransferase G9a is present in a SHP complex and enhances SHP inhibitory activity to suppress CYP7A1 expression. Besides cholesterol/bile acid homeostasis, FXR and SHP are involved in other metabolic pathways such as glucose homeostasis and fatty acid metabolism through bile acid signaling. Interestingly, it has been reported that the expression level of SHP was strikingly elevated in the liver of obese mice compared to normal mice. Also, it was reported that SHP-transgenic mice have significant features of fatty liver, such as lipid accumulation and elevated levels of hepatic triglycerides. These findings led me to ask how FXR enhances the level of SHP in the liver of obese mice without bile acid signaling. My recent findings suggest that histone acetyltransferase p300 is a critical FXR coactivator for SHP induction by acetylating core histones in response to bile acid treatment in normal mice. However, even without bile acid treatment, p300 can acetylate FXR, as well as core histones, at the native SHP promoter in obese mice, resulting in constitutively and highly elevated expression of SHP. These combined studies should lead to a better understanding how bile acid-responsive genes are regulated by the orphan nuclear receptors SHP and FXR and their cofactors in health and disease states.

Type of Resource

text

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Copyright 2008 Sungsoon Fang

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