The overall objective of this proposal is to define the metabolic consequences, interventions, and mechanisms of a novel signaling cascade involving retinoic acid receptor (RAR) and fibroblast growth factor 21 (FGF21) in non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases in the United States. Hepatic steatosis is an early and reversible stage of NAFLD, which can advance to irreversible cirrhosis and hepatocellular carcinoma with no effective therapies. Therefore, the discovery of novel metabolic pathways that present therapeutic targets is required to effectively manage NAFLD. As the major metabolite of vitamin A, all-trans-retinoic acid (RA) is a natural ligand of retinoic acid receptor (RAR) and is clinically used for anti-cancer therapy. However, the role of different RAR isotypes in regulating liver physiology and NAFLD is a novel and unexplored area. While the newly discovered hepatocyte-derived hormone FGF21 is emerging as a potential therapeutic target for treating metabolic disease, the upstream regulators of FGF21 remain largely unknown. Our recent discovery of a previously unrecognized crosstalk between RAR and FGF21 has changed this view and leads to a series of novel and exciting data that represent the core of our specific aims. Specifically, our results show that 1) FGF21 gene expression is induced by RAR?r RAR?ut not by RAR?; 2) RA increases fatty acid oxidation at least partially through FGF21 in vitro; 3) Hepatic overexpression of RAR?y an adenoviral gene delivery improves hepatic steatosis and insulin resistance in diet-induced obese mice; and 4) Hepatic overexpression of RAR?lso results in increased FGF21 production in mice. To extend these exciting observations, the Central Hypothesis is that hepatic RAR functions as a transcriptional regulator of FGF21 to maintain hepatic lipid homeostasis during prolonged fasting and to attenuate the progression of NAFLD. There are three Specific Aims. 1) To determine whether hepatic RAR regulates FGF21 induction and lipid homeostasis under nutrient deprivation conditions. State-of-the-art approaches including gene expression profiling analysis, metabolomics and lipidomics analyses will be conducted to identify new regulators and lipid metabolites involving RAR and/or FGF21 signaling. 2) To determine whether hepatic RAR slows the development of NAFLD and insulin resistance through FGF21 using in vivo adenoviral gene transfer targeting each RAR isotype and FGF21-/- mice. 3) To elucidate the molecular basis of the integrated signaling of hepatic RAR and FGF21 in de novo lipogenesis under in vivo and in vitro conditions of metabolic stress. Overall, accomplishing this proposal will establish th physiological role of an RAR-FGF21 signaling in the regulation of lipid homeostasis. These innovative experiments are expected to identify new therapeutic targets for the management of NAFLD and its related metabolic disease.

Public Health Relevance

The objective of this application is to define the metabolic consequences, interventions, and mechanisms of the integrated signaling of a vitamin A-related nuclear receptor called retinoic acid receptor (RAR) and a recently discovered hepatocyte-derived hormone called fibroblast growth factor 21 (FGF21) in non-alcoholic fatty liver disease (NAFLD). The proposed research will elucidate how liver activation of RAR by retinoic acid, a major metabolite of vitamin A, increases FGF21 production and maintains lipid homeostasis during prolonged starvation, as well as establish whether activation of hepatic RAR-FGF21 axis suppresses liver fat accumulation and slows the development and progression of NAFLD. The proposed research is relevant to the NIDDK mission and public health because the identification of such a novel crosstalk between RAR and FGF21 could provide the rationale for developing vitamin A-based nutritional and pharmacological interventions for NAFLD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
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University of Texas Health Science Center
Other Basic Sciences
Schools of Medicine
San Antonio
United States
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Chen, Hanqing; Shen, Feng; Sherban, Alex et al. (2018) DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Hepatology 68:496-514
Ramirez, Teresa; Li, Yong-Mei; Yin, Shi et al. (2017) Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol 66:601-609
Shen, Qiwei; Yang, Yeping; Liu, Wenjuan et al. (2017) Organ-specific alterations in circadian genes by vertical sleeve gastrectomy in an obese diabetic mouse model. Sci Bull (Beijing) 62:467-469
Li, Xiaoyu; Kover, Karen L; Heruth, Daniel P et al. (2017) Thioredoxin-interacting protein promotes high-glucose-induced macrovascular endothelial dysfunction. Biochem Biophys Res Commun 493:291-297
Han, Jingyan; Weisbrod, Robert M; Shao, Di et al. (2016) The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells. Redox Biol 9:306-319
Gong, Qi; Hu, Zhimin; Zhang, Feifei et al. (2016) Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. Hepatology 64:425-38
Luo, Ting; Nocon, Allison; Fry, Jessica et al. (2016) AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes 65:2295-310
Li, Xiaoyu; Kover, Karen L; Heruth, Daniel P et al. (2015) New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells. Mol Endocrinol 29:1184-94
Li, Yu; Wong, Kimberly; Giles, Amber et al. (2014) Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 146:539-49.e7