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.