Regulation of Nuclear Import/Export of Carbohydrate Response Element-binding Protein (ChREBP)

Abstract

SummaryNowadays few people consider finding their way in unfamiliar areas a problem as a GPS (Global Positioning System) combined with some simple map software can easily tell you how to get from A to B. Although this opportunity has only become available during the last decade, recent experiments show that long-distance migrating animals had already solved this problem. Even after displacement over thousands of kilometres to previously unknown areas, experienced but not first time migrant birds quickly adjust their course toward their destination, proving the existence of an experience-based GPS in these birds. Determining latitude is a relatively simple task, even for humans, whereas longitude poses much larger problems. Birds and other animals however have found a way to achieve this, although we do not yet know how. Possible ways of determining longitude includes using celestial cues in combination with an internal clock, geomagnetic cues such as magnetic intensity or perhaps even olfactory cues. Presently, there is not enough evidence to rule out any of these, and years of studying birds in a laboratory setting have yielded partly contradictory results. We suggest that a concerted effort, where the study of animals in a natural setting goes hand-in-hand with lab-based study, may be necessary to fully understand the mechanism underlying the long-distance navigation system of birds. As such, researchers must remain receptive to alternative interpretations and bear in mind that animal navigation may not necessarily be similar to the human system, and that we know from many years of investigation of long-distance navigation in birds that at least some birds do have a GPS -but we are uncertain how it works.

Transcriptional regulation of hepatic lipogenesis

“…ChREBP contains both a low glucose inhibitory domain (LID) and a glucose response activation conserved element (GRACE). LID inhibits the ChREBP transactivation activity conferred by GRACE, and this inhibition is lifted under high glucose conditions 93, 98, 99 . Therefore, ChREBP would be modified in a manner that relieves the repressive intramolecular interaction in high glucose condition.…”

“…In addition, ChREBP phosphorylation at S586 by AMPK also decreases its DNA binding activity 92 . ChREBP phosphorylated by PKA at S140 and S196 binds 14-3-3 with higher affinity to retain ChREBP in the cytosolic compartment 93, 94 . In high glucose conditions, ChREBP is dephosphorylated to become an active form and to translocate into nucleus to increase ChREBP binding to its response element 91 .…”

Energy Metabolism in the Liver

“…2B), resulting in nuclear export and inactivation of ChREBP in the liver (44, 47). Phosphorylated ChREBP binds to 14-3-3 and is retained in the cytoplasm (163, 222). Glucose is a potent activator of ChREBP.…”

Mechanisms of transcriptional control of glucose metabolism in hepatocytes

“…При голодании, когда концентрация глюкозы в плазме понижена, а уровень жирных кислот повышен, проис-ходит фосфорилирование остатка Ser196 в ChREBP под действием протеинкиназы А. Это приводит к связыва-нию транскрипционного фактора с адаптерным белком 14-3-3, его удалению из ядра и инактивации [53]. Повы-шение уровня внутриклеточной глюкозы приводит к уве-личению концентрации ее производных, в частности ксилулозо-5-фосфата, образующегося в пентозофосфат-ном пути.…”

“…Предположительно, селективный нокаут гена FOXO1 в печени может влиять на чувствительность к инсулину в периферических тка-нях за счет изменения продукции специфических пече-ночных факторов, обеспечивающих регуляцию действия инсулина на организм [17][18][19]. При этом изменение активности этих транскрипционных факторов в экспе-риментальных моделях успешно регулируется не только за счет нокаута целевых транскрипционных факторов, но и за счет механизмов их посттрансляционных моди-фикаций [28,42,53]. Эти находки открывают широкий диапазон потенциальных терапевтических мишеней для лечения диабета и других заболеваний, связанных с нарушением обмена глюкозы.…”