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PWE-112 Maternal Obesity Promotes Offspring Non-Alcoholic Fatty Liver Disease (Nafld) Through Disruption of Endoplasmic Reticulum Homeostasis
  1. J Soeda1,
  2. A Mouralidarane1,
  3. S Ray1,2,
  4. R Carter1,
  5. G Fusai3,
  6. M Novelli4,
  7. J Pombo5,
  8. A Bocioanowska5,
  9. D Sugden5,
  10. L Poston5,
  11. P Taylor5,
  12. J Oben1,2
  1. 1Institute of Liver & Digestive Health, University College London
  2. 2Gastroenterology, Guy’s & St Thomas’ Hospitals
  3. 3Hepatobiliary Surgery & Liver Transplantation, Royal Free Hospital
  4. 4Department of Pathology, University College London
  5. 5Division of Women’s Health, King’s College London, London, UK


Introduction We have previously shown that maternal obesity (MO) programmes offspring obesity and consequent liver disease (non-alcoholic fatty liver disease, NAFLD) but involved mechanisms are unclear. Accumulating evidence suggests endoplasmic reticulum (ER) stress induced unfolded protein response (UPR) plays a central role in the pathogenesis of steatosis and subsequent non-alcoholic steatohepatitis (NASH). However, little is known about the role of UPR in developmentally programmed NAFLD.

Methods C57BL6 mice were fed standard or obesogenic diet (OD) for 6 weeks prior to pregnancy and throughout pregnancy and lactation. Litters were weaned onto standard or OD to produce 4 groups. Animals were sacrificed at 6 months. Blood and tissue samples were collected to assess the liver phenotype and expression analysis of UPR related proteins and genes.

Results Offspring exposed to MO and a post-weaning OD (OffOb-OD) developed profound NAFLD compared to those exposed to post-partum (OffCon-OD) or the control group (OffCon-SC), as assessed by raised ALT (p < 0.001) and NAFLD Activity Score (p < 0.01). Among 3 proximal sensors of ER stress, PERK protein expression and phospho eIF-2alpha were specifically increased in OffOb-OD (p < 0.05). ATF6 cleavage and spliced form of XBP-1 were observed in all groups except for OffCon-SC. Phopho SAPK/JNK, CHOP, and LC3BII protein expression were significantly increased in OffOb-OD. Furthermore, hepatocytes apoptosis as detected by TUNEL and active capase-3 staining in OffOb-OD. These results indicate that unresolved UPR is significantly activated in OffCon-OD. However, GRP78, a major ER chaperone and central regulator for ER stress, was significantly downregulated in OffOb-OD. UPR induced chaperon (GRP94) and ER-associated protein degradation related gene (HERP and EDEM) were downregulated in OffCon-OB and OffOb-OD. Furthermore rhythmic expression of GRP78 and HERP were blunted in OffOb-OD.

Conclusion MO and a post-natal obesogenic diet profoundly disrupted ER homeostasis in offspring. Disrupted ER homeostasis may be involved in the propagation of NAFLD.

Disclosure of Interest None Declared.

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