The long-term objectives of this project are to determine the contribution of cholangiocyte lipoapoptosis to non-alcoholic fatty liver disease (NAFLD). Free fatty acid-induced apoptosis in the liver is a recognized aspect of hepatocyte injury;however cholangiocyte apoptosis has not been examined. This project will investigate cholangiocyte lipoapoptosis in NAFLD with an initial goal to determine critical apoptosis pathways and protective strategies. Preliminary data demonstrate that free fatty acids induced expression of proapoptotic miR-34a, c-Jun N-terminal kinase (JNK), and apoptosis in cultured cholangiocytes, and that signaling by palmitoleate prevented lipoapoptosis. The central hypothesis is that toxic free fatty acids contribute to biliary injury in NAFLD via proapoptotic microRNAs and the dietary molecule palmitoleate is protective against biliary lipoapoptosis.
The specific aims are to: (1) elucidate lipoapoptosis signaling in cholangiocytes regulated at the mitochondrial level and mitigated by palmitoleate;(2) identify the signaling pathway by which free fatty acids activate miR-34a;and (3) demonstrate cholangiocyte lipoapoptosis in clinically relevant liver disease and link this with proapoptotic microRNA signaling. A model of high-fat diet-induced obesity and liver steatosis will be employed, as well as liver samples from patients with NAFLD. Protection by dietary palmitoleate or genetic deficiency of miR-34a in the mouse will be tested. Completion of these aims will demonstrate the role of cholangiocyte lipoapoptosis and miR-34a in fatty liver injury, providing an opportunity to target this microRNA in human disease. Thus, this project has strong health relatedness by focusing on the clinically relevant cell death pathways present in the liver of patients. The project is closely related to the focus of the proposed Center, which is the discovery of signaling pathways through which nutrients and bioactive food compounds prevent, ameliorate, and treat obesity-related diseases, particulariy cardiovascular disease, diabetes, and NAFLD. Through advanced molecular, biochemical, and cell biological approaches to manipulate lipoapoptosis and miR-34a, this study will provide a foundation for a new line of inquiry in fatty liver injury to define the role of biliary cell death in disease.

Public Health Relevance

With the increase in obesity and metabolic syndrome in recent years, fatty liver injury is a growing health concern that in severe cases can lead to cirrhosis and liver failure. This project will study how cell death in bile duct epithelial cells contributes to non-alcoholic fatty liver disease. Successful completion of this project will define a role for these cells in fatty liver injury and may lead to new directions in therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-C (C1))
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University of Nebraska Lincoln
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Natarajan, Sathish Kumar; Muthukrishnan, Ezhumalai; Khalimonchuk, Oleh et al. (2017) Evidence for Pipecolate Oxidase in Mediating Protection Against Hydrogen Peroxide Stress. J Cell Biochem 118:1678-1688
Natarajan, Sathish Kumar; Rasineni, Karuna; Ganesan, Murali et al. (2017) Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease. Curr Mol Pharmacol 10:237-248
Perez-Muñoz, Maria Elisa; Arrieta, Marie-Claire; Ramer-Tait, Amanda E et al. (2017) A critical assessment of the ""sterile womb"" and ""in utero colonization"" hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5:48
Gomes-Neto, João Carlos; Mantz, Sara; Held, Kyler et al. (2017) A real-time PCR assay for accurate quantification of the individual members of the Altered Schaedler Flora microbiota in gnotobiotic mice. J Microbiol Methods 135:52-62
Shu, Jiang; Silva, Bruno Vieira Resende E; Gao, Tian et al. (2017) Dynamic and Modularized MicroRNA Regulation and Its Implication in Human Cancers. Sci Rep 7:13356
Farris, Eric; Brown, Deborah M; Ramer-Tait, Amanda E et al. (2017) Chitosan-zein nano-in-microparticles capable of mediating in vivo transgene expression following oral delivery. J Control Release 249:150-161
Cadaret, Caitlin N; Beede, Kristin A; Riley, Hannah E et al. (2017) Acute exposure of primary rat soleus muscle to zilpaterol HCl (?2 adrenergic agonist), TNF?, or IL-6 in culture increases glucose oxidation rates independent of the impact on insulin signaling or glucose uptake. Cytokine 96:107-113
Shradhanjali, Akankshya; Riehl, Brandon D; Lee, Jeong Soon et al. (2017) Enhanced cardiomyogenic induction of mouse pluripotent cells by cyclic mechanical stretch. Biochem Biophys Res Commun 488:590-595
Zempleni, Janos; Aguilar-Lozano, Ana; Sadri, Mahrou et al. (2017) Biological Activities of Extracellular Vesicles and Their Cargos from Bovine and Human Milk in Humans and Implications for Infants. J Nutr 147:3-10
Song, Yongyan; Zhao, Miaoyun; Cheng, Xiao et al. (2017) CREBH mediates metabolic inflammation to hepatic VLDL overproduction and hyperlipoproteinemia. J Mol Med (Berl) 95:839-849

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