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Toxicol Appl Pharmacol. 2014 Jan 15;274(2):263-73. doi: 10.1016/j.taap.2013.11.009. Epub 2013 Nov 22.

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats.

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Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy, France.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071, China. Electronic address:


Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE+ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE+HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE+HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a "two-programming" hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is "the first programming", and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as "the second programming".


ACCα; ACTB; ADIPOR2; AMPKα; APOB; CORT; CPT1α; Catch-up growth; FASN; FOXO1; G6Pase; GAPDH; GC; GC–MS; GLUT2; GSK3β; Glucocorticoid–insulin-like growth factor-1 axis; HFD; HMG-CoA reductase; HMGCR; HNF4; HPRT1; IGF-1; IGF-1 receptor; IGF-1R; IGFBP3; INSR; IRS1; IRS2; IUGR; JAK2; Janus kinase 2; LEPR; MS; MTTP; NAFLD; ND; Non-alcoholic fatty liver disease; PEE; PPARα; Prenatal ethanol exposure; SREBP1c; TG; Two-programming hypothesis; acetyl-CoA carboxylase α; adenosine monophosphate activated protein kinase α; adiponectin receptor 2; apolipoprotein B; carnitine palmitoyltransferase 1α; corticosterone; fatty acid synthase; fork-head transcriptional factor O1; gas chromatography–mass spectrometry; glucocorticoid; glucose transporter 2; glucose-6-phosphatase; glyceraldehyde-phosphate dehydrogenase; glycogen synthase kinase 3β; hepatocyte nuclear factor 4; high-fat diet; hypoxanthine phosphoribosyltransferase 1; insulin receptor; insulin receptor substrate 1; insulin receptor substrate 2; insulin-like growth factor binding protein 3; insulin-like growth factor-1; intrauterine growth retardation; leptin receptor; mTORC2; mammalian target of rapamycin complex 2; metabolic syndrome; microsomal triglyceride transfer protein; non-alcoholic fatty liver disease; normal diet; peroxisome proliferator activated receptor α; prenatal ethanol exposure; sterol regulatory element binding protein-1c; triglyceride; β actin

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