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Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Our previous study demonstrated that prenatal food restriction (PFR) could induce the dysfunction of the hypothalamic-pituitary-adrenal axis and glucocorticoid-related glucose and lipid metabolic alterations in adult offspring rats., Aim of the Study: To investigate the intrauterine programming mechanism of adrenal dysfunction in the PFR offspring rats., Methods: From gestational days (GDs) 11-20, pregnant Wistar rats were fed a restricted diet (50% of the daily food intake of control rats, 60 g/kg·d). Some were executed at GD20, while the others survived to full-term delivery; all pups were fed a high-fat diet (HFD) after weaning. The serum corticosterone concentration, expression level of adrenal steroidal synthetase, and insulin-like growth factor 1 (IGF1) signaling pathway were tested., Results: We confirmed that the fetal body weight of the PFR group was lower than that of the control group, and the mRNA expression of adrenal steroidogenic acute regulatory protein, cytochrome P450 cholesterol side chain cleavage, 3β-hydroxysteroid dehydrogenase, and steroid 11β-hydroxylase (P450c11) were decreased in the PFR fetal rats. The maternal and fetal serum corticosterone levels were significantly increased in the PFR groups. Furthermore, the expression of the adrenal IGF1 signaling pathway (including IGF1, IGF1R, and Akt1) was suppressed. However, after a post-weaning HFD, the body weight gain rates and serum corticosterone levels were elevated, and the expression of adrenal steroid 21-hydroxylase and P450c11, as well as the IGF1 signaling pathway, were significantly increased in the PFR group., Conclusions: These results showed that a higher level of circulation corticosterone by PFR in utero inhibited adrenal IGF1 signaling and steroidogenesis, whereas post-weaning HFD induced adrenal steroidogenesis by an enhanced IGF1 signaling., (Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.)