Acute Fatty Liver of Pregnancy (AFLP) is associated with the accumlation of 3-hydroxy fatty acids (3-HFAs), acute maternal liver disfunction, and significant maternal and perinatal mortality in the third trimester of pregnancy. Mothers with fetuses defective in the enzyme long chain 3-hydroxy acyl CoA dehydrogenase (LCHAD) develop AFLP. LCHAD deficiency leads to accumulation of 3-HFAs in the placenta that are shunted into maternal circulation damaging the maternal liver.
The aim of the proposed research is to fill a gap in knowledge about whether 3-HFA is a causal factor in placenta and liver lipotoxicity observed with AFLP and, if it is, whether that information can be used in developing a therapy to treat 3-HFA-induced lipotoxicity. Preliminary data suggest that 3-HFAs exposure to hepatocyte cells induces lipoapoptosis and 3-HFAs exposure to placental trophoblasts induce necroptosis (i.e. inflammatory cell death). Initial studies indicate palmitoleate can protect against both 3-HFA-induced hepatocyte lipoapoptosis and trophoblast necroptosis in cell culture. The mechanism of 3 HFA-induced hepatocyte lipoapoptosis appears to involve: 1) pro-apoptotic FoxO3 nuclear activation; and 2) increased expression of FoxO3 downstream targets, like p53 upregulated modulator of apoptosis (PUMA). The central hypotheses are that: 1) toxic 3-HFAs accumulating during AFLP lead to placental trophoblast necroptosis and hepatocyte lipoapoptosis, and 2) dietary palmitoleate supplementation can mitigate 3-HFA-induced placental trophoblast and hepatocyte lipotoxicity and injury. The hypotheses will be tested through two specific aims (SAs): 1) elucidate the role of 3-HFA in lipotoxicity and its underlying mechanisms in of 3-HFA-induced lipotoxicity in the placenta and liver; and 2) mitigate 3-HFA-induced placental trophoblast and hepatocyte lipotoxicity with dietary palmitoleate supplementation. Hepatocytes and placental trophoblast cells will be treated in the presence or absence of 3-HFAs and examined for mitochondrial structure and function, pro- apoptotic mediators and biochemical markers of cell death and MAPK activation as a measure of lipotoxicity. The causal link for placenta and the liver lipotoxicity in AFLP with 3-HFA accumulation will be determined by injecting 3-HFAs in wild-type C57BL/6 pregnant mice to induce lipotoxicity and analyzing the markers of liver and placental lipotoxicity along with markers for cell death. Protection against trophoblast necroptosis will be studied via the activation of receptor interacting protein kinase 1, a key mediator of necroptosis, whereas protection against hepatocyte lipoapoptosis will be studied by investigating FoxO3 nuclear activation along with the Wnt3a-dependent cell survival pathways. The outcome of this project will contribute to Dr. Natajaran's long- term goal to develop foods high in palmitoleate as a therapeutic approach to mitigate placental and maternal liver injury in AFLP, which aligns with the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD)'s thematic focus of identifying biological, primarily food-borne signals that prevent, treat, and cure obesity-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM104320-06
Application #
9795742
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Nebraska Lincoln
Department
Type
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68503
Kittana, Hatem; Quintero-Villegas, Maria I; Bindels, Laure B et al. (2018) Galactooligosaccharide supplementation provides protection against Citrobacter rodentium-induced colitis without limiting pathogen burden. Microbiology 164:154-162
Neilsen, Beth K; Chakraborty, Binita; McCall, Jamie L et al. (2018) WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage. BMC Cancer 18:673
Kuss, Mitchell; Kim, Jiyoung; Qi, Dianjun et al. (2018) Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function. Acta Biomater 71:486-495
Yates, Dustin T; Petersen, Jessica L; Schmidt, Ty B et al. (2018) ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward-How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe. J Anim Sci 96:2987-3002
Natarajan, Sathish Kumar; Ibdah, Jamal A (2018) Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy. Int J Mol Sci 19:
Camara Teixeira, Daniel; Cordonier, Elizabeth L; Wijeratne, Subhashinee S K et al. (2018) A cell death assay for assessing the mitochondrial targeting of proteins. J Nutr Biochem 56:48-54
Hakguder, Zeynep; Shu, Jiang; Liao, Chunxiao et al. (2018) Genome-scale MicroRNA target prediction through clustering with Dirichlet process mixture model. BMC Genomics 19:658
McAtee, Caitlin O; Booth, Christine; Elowsky, Christian et al. (2018) Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling. Matrix Biol :
Manca, Sonia; Upadhyaya, Bijaya; Mutai, Ezra et al. (2018) Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Sci Rep 8:11321
E Silva, Bruno Vieira Resende; Rad, Milad Ghiasi; Cui, Juan et al. (2018) A Mobile-Based Diet Monitoring System for Obesity Management. J Health Med Inform 9:

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