Retinoids have broad effects including development, growth, cell death, and anti-oxidation. Their actions have been extensively studied in the skin, eye, and in many types of cancer. The liver is a major retinoic acid (RA) target site. Surprisingly, the action of RA in the liver has received very little attention. Our data generated in the past 10 years have uncovered many novel roles of retinoids in the liver. We showed that in the liver retinoids and their receptors have a broad spectrum of actions ranging from xenobiotic biotransformation to cholesterol, fatty acid, bile acid, carbohydrate, and amino acid homeostasis. In addition, hepatic retinoid signaling regulates cell proliferation and apoptosis as well as inflammation. Thus, we hypothesize that RA and its receptors regulate liver metabolism and function in general. The objective for the current application is twofold: to provide a hepatic genome-wide RA receptor target-gene profile in a gender-specific manner and to elucidate the mechanism by which RA and its receptors regulate gene transcription and expression. Among the diverse pathways, we propose to focus on studying the role of RA/receptors in regulating lipid homeostasis because hepatocyte RXR1 (retinoid x receptor 1) deficiency increases serum lipids and RA treatment reduces them in vivo. Furthermore, lack of hepatic RXR1 increases the susceptibility to develop steatosis and steatohepatitis.
Three specific aims are proposed to study the global effect of RA/receptors in the liver and the underlying mechanisms.
Aim 1 determines genome-wide RA/receptor target genes/pathways in the liver in a gender- specific manner using ChIP-sequencing and microarray analysis. The generated data may account for gender difference in liver function and susceptibility to liver disease.
Aim 2 studies the mechanism by which retinoid- mediated pathways regulate lipid homeostasis. We propose to study the mechanisms that regulate two clusters of lipid homeostasis genes, which either do or do not respond to RA but both depend on hepatic RXR1 for their expressions. The transcriptional machinery, which dictates RA responsiveness, will be elucidated.
Aim 3 studies the basal and RA-induced transcriptional machinery mediated by hepatic RXR1. We focus on PDK4, RAR2, and Cyp26a1 because our novel data show that these genes are induced by RA treatment as well as RXR1 deficiency. These genes have functional significance in either lipid homeostasis or RA efficacy. How retinoid signaling is controlled at the basal and RA-regulated level will be determined. The proposed study may be the first attempt to uncover the fundamental effects of retinoid signaling within the liver with an emphasis on lipid homeostasis. The generated data will have a huge impact on cancer, metabolic syndrome, diabetes, and cardiovascular disease as well as toxicology.

Public Health Relevance

We show that retinoids and their receptors have a broad spectrum of actions ranging from xenobiotic biotransformation to cholesterol, fatty acid, bile acid, carbohydrate, and amino acid homeostasis in the liver. The proposed project will profile hepatic genome-wide RA receptor target genes in a gender-specific manner and elucidate the mechanism by which RA and its receptors regulate gene expression and transcription. The generated data will have a significant impact on conditions including but not limited to cancer, toxicology, metabolic syndrome, diabetes, and cardiovascular disease.

National Institute of Health (NIH)
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Special Emphasis Panel (ZRG1)
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Serrano, Jose
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University of California Davis
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Liu, Hui-Xin; Rocha, Clarissa Santos; Dandekar, Satya et al. (2016) Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration. J Hepatol 64:641-50
Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne (2016) Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration. Oncotarget 7:1096-106
Liu, Hui-Xin; Keane, Ryan; Sheng, Lili et al. (2015) Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol 63:1502-10
Yang, Fan; Hu, Ying; Liu, Hui-Xin et al. (2015) MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem 290:6507-15
Liu, Hui-Xin; Hu, Ying; French, Samuel W et al. (2015) Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis. Oncotarget 6:9686-700
Hu, Ying; Chau, Thinh; Liu, Hui-Xin et al. (2015) Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis. Mol Cancer Res 13:281-92
Liu, Hui-Xin; Ly, Irene; Hu, Ying et al. (2014) Retinoic acid regulates cell cycle genes and accelerates normal mouse liver regeneration. Biochem Pharmacol 91:256-65
Hu, Ying; Zhan, Qi; Liu, Hui-Xin et al. (2014) Accelerated partial hepatectomy-induced liver cell proliferation is associated with liver injury in Nur77 knockout mice. Am J Pathol 184:3272-83
He, Yuqi; Tsuei, Jessica; Wan, Yu-Jui Yvonne (2014) Biological functional annotation of retinoic acid alpha and beta in mouse liver based on genome-wide binding. Am J Physiol Gastrointest Liver Physiol 307:G205-18
Yang, Fan; He, Yuqi; Liu, Hui-Xin et al. (2014) All-trans retinoic acid regulates hepatic bile acid homeostasis. Biochem Pharmacol 91:483-9

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