Dissociation of Inositol-requiring Enzyme (IRE1α)-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice

Jurczak, Michael J.; Lee, Ann–Hwee; Jornayvaz, François R.; Lee, Hui Young; Birkenfeld, Andreas L.; Guigni, Blas A.; Kahn, Mario; Samuel, Varman T.; Glimcher, Laurie H.; Shulman, Gerald I.

doi:10.1074/jbc.m111.316760

Cited by 134 publications

(116 citation statements)

References 54 publications

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“…XBP1s consistently induced plasma TG levels in all mouse models described in this manuscript. This is in line with previous reports showing that depletion of hepatic XBP1s reduced TG secretion (24,44). We propose that enhanced breakdown of hepatic lipid droplets and reduction in hepatic TG storage leads to redistribution of lipids from the liver to the periphery, thereby contributing to the rise in plasma TG levels in DIO and ob/ob mice.…”

Section: Discussionsupporting

confidence: 81%

XBP1s Is an Anti-lipogenic Protein

Herrema

Zhou

Zhang

et al. 2016

Journal of Biological Chemistry

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Endoplasmic reticulum (ER) stress has been shown to contribute to various metabolic diseases, including non-alcoholic fatty liver disease and type 2 diabetes. Reduction of ER stress by treatment with chemical chaperones or overexpression of ER chaperone proteins alleviates hepatic steatosis. Nonetheless, X-box binding protein 1s (XBP1s), a key transcription factor that reduces ER stress, has been proposed as a lipogenic transcription factor. In this report, we document that XBP1s leads to suppression of lipogenic gene expression and reduction of hepatic triglyceride and diacylglycerol content in livers of dietinduced obese and genetically obese and insulin-resistant ob/ob mice. Furthermore, we also show that PKC⑀ activity, which correlates with fatty liver and which causes insulin resistance, was significantly reduced in diet-induced obese mice. Finally, we have shown that XBP1s reduces the hepatic fatty acid synthesis rate and enhances macrolipophagy, an initiating step in lipolysis. Our results reveal that XBP1s reduces hepatic lipogenic gene expression and improves hepatosteatosis in mouse models of obesity and insulin resistance, which leads us to conclude that XBP1s has anti-lipogenic properties in the liver.

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Section: Discussionsupporting

confidence: 81%

XBP1s Is an Anti-lipogenic Protein

Herrema

Zhou

Zhang

et al. 2016

Journal of Biological Chemistry

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“…In CypD-KO mice, hepatic insulin resistance appears to be mainly secondary to ER stress modulation of hepatic lipogenesis and subsequent DAG-mediated activation of PKCε rather than to ER stressinduced JNK activation, at least in vitro. Whereas an unspecific effect of inhibitors could not be excluded, this result fits well with the mechanisms recently proposed for another mouse model of insulin resistance [28], as well as with recent data in human liver [23]. Nevertheless, we cannot exclude the possibility that other players could be involved in the insulinresistant phenotype of CypD-KO mice.…”

Section: Discussionsupporting

confidence: 72%

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

et al. 2015

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Aims/hypothesis Mitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca 2+ ) transfer between both organelles through the complex formed between the voltage-dependent anion channel, glucose-regulated protein 75 and inositol 1,4,5-triphosphate receptor (IP3R). We recently identified cyclophilin D (CYPD) as a new partner of this complex and demonstrated a new role for MAMs in the control of insulin's action in the liver. Here, we report on the mechanisms by which disruption of MAM integrity induces hepatic insulin resistance in CypD (also known as Ppif)-knockout (KO) mice. Methods We used either in vitro pharmacological and genetic inhibition of CYPD in HuH7 cells or in vivo loss of CYPD in mice to investigate ER-mitochondria interactions, inter-organelle Ca 2+ exchange, organelle homeostasis and insulin action. Results Pharmacological and genetic inhibition of CYPD concomitantly reduced ER-mitochondria interactions, inhibited inter-organelle Ca 2+ exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histaminestimulated Ca 2+ transfer from ER to mitochondria was blunted in isolated hepatocytes of CypD-KO mice and this was associated with an increase in ER calcium store. Interestingly, disruption of inter-organelle Ca 2+ transfer was associated with ER stress, mitochondrial dysfunction, lipid accumulation, activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)ε and insulin resistance in liver of CypD-KO mice. Finally, CYPD-related alterations of insulin signalling were mediated by activation of PKCε rather than JNK in HuH7 cells. Conclusions/interpretation Disruption of IP3R-mediated Ca 2+ signalling in the liver of CypD-KO mice leads to hepatic insulin resistance through disruption of organelle interaction and function, increase in lipid accumulation and activation of PKCε. Modulation of ER-mitochondria Ca 2+ exchange may thus provide an exciting new avenue for treating hepatic insulin resistance.

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“…Were performed as previously described (41). Briefly, following an overnight fast, catheterized mice were infused with 3-[ 3 H]glucose at a rate of 0.05 μCi/min for 120 min to determine basal glucose turnover.…”

Section: Methodsmentioning

confidence: 99%

Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo

Galbo¹,

Perry

Jurczak³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCe, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides.

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Dissociation of Inositol-requiring Enzyme (IRE1α)-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice

Cited by 134 publications

References 54 publications

XBP1s Is an Anti-lipogenic Protein

XBP1s Is an Anti-lipogenic Protein

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo

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