The role of X-box binding protein 1 in the hepatic response to refeeding in mice

Abstract

Abbreviations: Acc, acyl-CoA carboxylase; CHOP, C/EBP homologous protein; Dgat2, diacylglycerol acyl-transferase 2; Dr5, death receptor 5; Edem, endoplasmic reticulum degradation enhancing mannoside; eIF2, eukaryotic initiation factor 2; ERo1, endoplasmic reticulum oxidase 1; IRE1, inositol requiring enzyme 1; Scd-1, stearoyl-CoA desaturase 1; Trb3, Tribbles-related protein 3; UPR, unfolded protein response; XBP1, X-box binding protein 1.

Regulation of lipid metabolism by the unfolded protein response

“…The same publication showed that Xbp1s LKO mice had decreased plasma levels of TGs, due to an impaired secretion by the liver, in both fasting and refeeding states. This strengthened the idea that the function of XBP1s in hepatic lipid metabolism is not restricted to lipogenesis 74 . A similar observation was made during the characterization of a conditional postnatal Xbp1 KO in mice liver, in which decreased levels of plasma TGs, cholesterol and free FAs were observed in KO animals compared to controls 70 .…”

“…This strengthened the idea that the function of XBP1s in hepatic lipid metabolism is not restricted to lipogenesis. 74 A similar observation was made during the characterization of a conditional postnatal Xbp1 KO in mice liver, in which decreased levels of plasma TGs, cholesterol and free FAs were observed in KO animals compared to controls. 70 A possible explanation for these results came from a later study which showed that XBP1 overexpression was able to revert deficient secretion of TGs in hepatocytes from liver-specific Ern1a KO mice by increasing protein disulphide isomerase (PDI) expression.…”

“…In liver‐specific Xbp1 KO ( Xbp1 LKO) mice, hepatic XBP1s expression was required for the translation, but not transcription, of de novo lipogenesis genes such as Srebp1c , Fasn and Acac 74 . This effect was linked to a phospho‐eIF2α‐induced arrest in global translation, leading to the conclusion that, while XBP1s might not be necessary for the transcriptional induction of lipogenic genes, its activity is necessary to manage fasting and refeeding states in the liver 74 . The same publication showed that Xbp1s LKO mice had decreased plasma levels of TGs, due to an impaired secretion by the liver, in both fasting and refeeding states.…”

Preventive Effect of Apple Polyphenol Extract on High-Fat Diet-Induced Hepatic Steatosis in Mice through Alleviating Endoplasmic Reticulum Stress

“…65 Mice lacking hepatic XBP1 had markedly decreased mRNA levels of SREBP1, FAS, and ACC1. 66,67 It has been reported that the RNAi-mediated knockdown of ATF6 in hepatocytes could block fatty acid-induced SREBP-1c expression. 68 In this study, the expression of proteins related to ERS and lipogenesis were measured, and our findings agreed with those of previous studies.…”

Dysregulated lipid metabolism in colorectal cancer

“…The contribution of the other two arms of the UPR to the regulation of lipid metabolism is also evident. Inositol-requiring enzyme 1a (IRE1a) regulates lipid metabolism via X-box binding protein 1 (XBP1) and regulated IRE1dependent decay (RIDD), to control the transport of triglycerides and proliferator-activated receptor a (PPARa)-mediated lipolysis, and to promote lipid hydrolysis and prevent lipid storage, respectively [50][51][52]. Examples of the regulation of lipid metabolism through eukaryotic Initiation Factor 2 (eIF2a), ATF4 and C/EBP homologous protein (CHOP), which constitute downstream targets of protein kinase RNA-like ER Kinase (PERK) signaling, include lipogenesis, and FA elongation and FA desaturation [53,54].…”