Abstract
Endoplasmic reticulum (ER) stress, a cellular condition caused by the accumulation of unfolded proteins inside the ER, has been recognized as a major pathological mechanism in a variety of conditions, including cancer, metabolic and neurodegenerative diseases. Trefoil factor family (TFFs) peptides are present in different epithelial organs, blood supply, neural tissues, as well as in the liver, and their deficiency has been linked to the ER function. Complete ablation of Tff3 expression is observed in steatosis, and as the most prominent change in the early phase of diabetes in multigenic mouse models of diabesity. To elucidate the role of Tff3 deficiency on different pathologically relevant pathways, we have developed a new congenic mouse model Tff3−/−/C57BL6/N from a mixed background strain (C57BL6/N /SV129) by using a speed congenics approach. Acute ER stress was evoked by tunicamycin treatment, and mice were sacrificed after 24 h. Afterwards the effect of Tff3 deficiency was evaluated with regard to the expression of relevant oxidative and ER stress genes, relevant proinflammatory cytokines/chemokines, and the global protein content. The most dramatic change was noticed at the level of inflammation-related genes, while markers for unfolded protein response were not significantly affected. Ultrastructural analysis confirmed that the size of lipid vacuoles was affected as well. Since the liver acts as an important metabolic and immunological organ, the influence of Tff3 deficiency and physiological function possibly reflects on the whole organism.
Highlights
Proper protein folding and localization is crucial for protein function
Liver 2ti.s2s.uEexpwreasssicoonlloefcOtexdid2at4ivhe Satfrteesrs tMreaartkmereGnte.neUssing the SYBR green quantitative polymerase chain reaction method, we compared the levels of several ER stress (ERS) relevant genes: BIP, GRDP94, CHOP, ossXhf oWBwPTt1eah,dneEtdehDffaTEetffMcT3tm−o/a−ftnrTmdeffai3ActmedTeweFfin4ictt.hiaeCcnaotncimvydapotweandrittishhroeeonlueovtxoaTifdnmagtteEitnvrReeeSasetmtmxrepaesrrnsketsem.srGiagoreenknnereeressel,ax(wFtpiihvrgeieucshrsteoiwo3nWa) swltesavtCaseTtlmisRstoriencmlaiatiltocliyervered(eFtloiiengvuuatnhrnetetrael1inaAvtde)erds Wcotmmpiacreasbhleoiwnebdotthhamt iTcme gterneaottmypeenst. sTtmat-itsrteicaatelldy Wredt auncdedTtffh3e−/−emxpicreessshioonwoedf GaPsiXm1ilianrWgetn(e4.e5x5pfroelsds)ioannd Tleffv3e−l/−(F(i3g.5urfeol1dB))m
The novel congenic mouse strain Trefoil factor family 3 (Tff3)−/−/C57BL6NCrl is a valuable model for assessing the role of Tff3 deficiency on liver disease relevant pathways
Summary
Endoplasmic reticulum (ER) has the main role in the folding and dispatching of secretory and transmembrane proteins to the appropriate destinations. Various conditions, such as increased protein synthesis, decreased ER-associated degradation, disturbed lipid homeostasis, calcium efflux and oxidative stress, can lead to an accumulation of misfolded proteins, and subsequently trigger a condition known as ER stress (ERS) [1]. The adaptive mechanism activated in this situation is known as the unfolded protein response (UPR). The UPR forms a complex network mediated by three ER membrane-associated proteins, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 alpha (IRE1α) and activating transcription factor 6 alpha (ATF6α)
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