Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) precede ultimate liver failure. The current epidemic of childhood obesity has increased NAFLD in children, and the global form of NAFLD due to undernutrition occurs in lean individuals with insulin deficiency. This form is also seen in intra-uterine growth restricted (IUGR) infants who express postnatal cholestatic liver disease. Despite certain standard interventions, some infants at both extremes of malnutrition, progress to requiring liver transplantation in Western countries. Many infants succumb, awaiting organs and despite successful liver transplantation develop complications. Given this dismal outlook, it is essential to discover novel biomarkers and therapeutic targets towards preventing NAFLD before biochemical features manifest and clinical complications arise. To this end, we developed in rat gestational models, undernutrition induced IUGR and high fat (HF) diet induced postnatal obesity, both developed NAFLD. Preliminarily, the adult HF or IUGR offspring, both displayed increased hepatic and serum microRNA (miR)-122, a biomarker of hepatic damage in human adults. Similar to rat, miR-122 was detected in human umbilical cord and infant sera providing the possibility of predicting hepatic disease in large for gestational age (LGA) and IUGR high risk children. Two of the novel target genes that contain complementary sequences to miR-122 in their 3'-untranslated region (UTR) are nocturnin (Noc; rhythmic output gene) and Methyl-CP-binding protein 2 [Mecp2], a nuclear protein, that binds methylated CpG islands in gene promoters. Based on our preliminary novel observations related to miR-122, Noc and Mecp2, we hypothesize that 1) hepatic miR-122 via its target mRNAs, predicts subsequent NAFLD, and 2) postnatal suppression of miR-122 can reverse the subsequent trajectory of NAFLD, possibly translating a preventive therapeutic modality to high risk children. To test these hypotheses, we plan to employ rat models of gestational exposure to a HF diet (HF offspring) versus calorie restriction (IUGR), both with postnatal exposure to a HF diet, and human umbilical cord and infant sera in the following specific aims: 1. To investigate the mechanistic role of miR-122 and its target genes Noc and Mecp2 in enhancing hepatic lipid synthesis resulting in NAFLD. 2. To examine the effect of postnatal in-vivo suppression of miR-122 on key hepatic gene expression thereby aborting development of NAFLD. 3. To explore the possibility of miR-122 serving as a biomarker in a) human LGA and IUGR infants by detection and quantification in umbilical cord serum and b) serum from older infants with established liver injury. Results of our proposed studies will provide a biomarker by which LGA and IUGR infants can be tracked for their hepatic health and a pre-clinical therapeutic strategy that prevents NAFLD. These results will provide tools necessary to translate our findings to high-risk infants towards ameliorating subsequent NAFLD, a pre-runner of liver failure with its morbidity and mortality.

Public Health Relevance

The dismal outlook of the increasing incidence of liver failure due to non-alchoholic fatty liver disease (NAFLD) in children forces us to investigate biomarkers that appear well before biochemical indices of liver failure, prompting the possibility of developing liver damage in the future. This would offer a window during which therapies can be introduced to prevent this trajectory. We believe that a small microRNA-122 produced by the liver and found in the blood will be this biomarker and suppression of this microRNA-122 may provide therapeutic relief of such disorders that affect and damage the liver in children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041230-14
Application #
9413353
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Raiten, Daniel J
Project Start
2001-08-05
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Thamotharan, Shanthie; Chu, Alison; Kempf, Katie et al. (2017) Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport. PLoS One 12:e0176493
Chu, Alison; Thamotharan, Shanthie; Ganguly, Amit et al. (2016) Gestational food restriction decreases placental interleukin-10 expression and markers of autophagy and endoplasmic reticulum stress in murine intrauterine growth restriction. Nutr Res 36:1055-1067
Devaskar, Sherin U; Chu, Alison (2016) Intrauterine Growth Restriction: Hungry for an Answer. Physiology (Bethesda) 31:131-46
Ganguly, Amit; Touma, Marlin; Thamotharan, Shanthie et al. (2016) Maternal Calorie Restriction Causing Uteroplacental Insufficiency Differentially Affects Mammalian Placental Glucose and Leucine Transport Molecular Mechanisms. Endocrinology 157:4041-4054
Gibson, Leena Caroline; Shin, Bo-Chul; Dai, Yun et al. (2015) Early leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in the pre- and postnatal calorie-restricted female rat offspring. J Neurosci Res 93:902-12
Freije, William A; Thamotharan, Shanthie; Lee, Regina et al. (2015) The hepatic transcriptome of young suckling and aging intrauterine growth restricted male rats. J Cell Biochem 116:566-79
Garg, Meena; Thamotharan, Manikkavasagar; Becker, Dorothy J et al. (2014) Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1). Pediatr Diabetes 15:511-8
Braga, Melissa; Reddy, Srinivasa T; Vergnes, Laurent et al. (2014) Follistatin promotes adipocyte differentiation, browning, and energy metabolism. J Lipid Res 55:375-84
Calkins, Kara L; Dunn, James C Y; Shew, Stephen B et al. (2014) Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr 38:682-92
Raychaudhuri, Nupur; Thamotharan, Shanthie; Srinivasan, Malathi et al. (2014) Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression. J Nutr Biochem 25:1066-76

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