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Microarray analysis of developmentally programmed hepatic steatosis in Undernourishment in utero mouse model

ABSTRACT: Nutritional imbalances in the early developmental period have an impact on the long-term risk of developing non-alcoholic fatty liver disease (NAFLD). In the present study, we demonstrated that tauroursodeoxycholic acid (TUDCA), a secondary bile acid, and markedly ameliorated hepatic steatosis in a mouse model of undernourishment in utero. Herein, we studied the effect of maternal caloric restriction on genetic expression by microarray analysis among 3 different time points of independent cohorts. Cohort 1 (at 9 weeks; without HFD), cohort 2 (at 17 weeks; with HFD), and cohort 3 (at 22 weeks; HFD with or without the TUDCA treatment) (Muramatsu-Kato et al., 2015). We compared the alteration in gene expression between NN pups and UN pups before and after postnatal high-fat diet (HFD) at 9 weeks and 17 weeks. Later we studied the TUDCA treatment responce on NN pups and UN pups.

ORGANISM(S): Mus musculus

PROVIDER: GSE123733 | GEO | 2019/11/19

REPOSITORIES: GEO

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Project description:Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are all increased in the lungs of neonatal rat pups raised in hyperoxia (HOX, >90% O2), an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in HOX rat pups. To determine the relationship between OS, MPO, and ER stress in BPD we treated Sprague-Dawley neonatal rat pups with Tunicamycin (Tun) or with HOX. Tun directly induces ER stress and simplifies neonatal lung alveolarization. Previously, we showed that HOX induces a cycle of destruction that we hypothesize through increased OS, MPO, and ER stress to induce BPD. To inhibit ER stress specifically, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO we used N-acetyl-lysyltyrosylcysteine-amide (KYC), a systems pharmacology agent. Lung structure was studied morphometrically. ER stress was detected using immunofluorescence (IF), transcriptomic, proteomic, and electron microscopic analyses. Increased ER stress was observed in the lungs of HOX rat pups and also in human BPD lungs by IF. Morphometric and proteomic studies of rat lungs showed that Tun treatment decreased lung complexity and increased ER stress and BPD severity. The fact that TUDCA improved lung complexity in Tun-treated neonatal rat pups, and decreased BPD induced by HOX provides strong support for the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of both Tun- and HOX-treated neonatal rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's effective inhibition of ER stress in the lungs of Tun-treated rat pups provides additional support for the idea that MPO-induced ER stress plays a direct causal role in BPD. Thus, ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impaired neonatal lung growth and development. The encouraging effect of TUDCA indicates chemical chaperone has the potential in treating BPD. Using multiomic data to investigate the role of endoplasmic reticulum stress in the development of BPD in rat model.

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Microarray analysis of developmentally programmed hepatic steatosis in Undernourishment in utero mouse model

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