The integrated stress response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by normalization of protein synthesis. Here, we report a dramatically different response during chronic ER stress. This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF3-dependent translation initiation mechanism, resulting in partial, but not complete, translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits "foamy cell" development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.

• Klíčová slova
• ER stress, PERK, eIF2, eIF2B, eIF3, integrated stress response, mRNA translation, protein synthesis, stress signaling, unfolded protein response,
• MeSH
• časové faktory MeSH
• eukaryotický iniciační faktor 3 genetika   metabolismus   MeSH
• fenotyp MeSH
• fibroblasty metabolismus   patologie   MeSH
• genetická transkripce * MeSH
• HEK293 buňky MeSH
• homeostáze proteinů MeSH
• kinasa eIF-2 genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• myši MeSH
• otevřené čtecí rámce MeSH
• přeprogramování buněk MeSH
• proteosyntéza * MeSH
• RNA interference MeSH
• signální transdukce MeSH
• stres endoplazmatického retikula * MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• eukaryotický iniciační faktor 3 MeSH
• kinasa eIF-2 MeSH
• messenger RNA MeSH
• PERK kinase MeSH Prohlížeč

We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.

• Klíčová slova
• ER stress, NAFLD, Obesity, circadian rhythm, developmental programming,
• MeSH
• chaperon endoplazmatického retikula BiP MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• endoplazmatické retikulum fyziologie   MeSH
• fyziologický stres účinky léků   MeSH
• homeostáza MeSH
• játra účinky léků   MeSH
• krmivo pro zvířata analýza   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita chemicky indukované   metabolismus   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH