Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice

Zhang, Cheng; Chen, Xi; Zhu, Ren-Min; Zhang, Ying; Yu, Tao; Wang, Hua; Zhao, Hui; Zhao, Mingqiu; Ji, Yan-Li; Chen, Yuan-Hua; Meng, Xiu-Hong; Wei, Wei; D, Xu

doi:10.1016/j.toxlet.2012.06.002

Cited by 93 publications

(56 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, fat accumulation in the liver of CypD-KO mice seems to be related to both a reduction in lipid oxidation (based on reduction in Cpt1 expression) and an induction of de novo lipogenesis (based on induction of lipogenic genes), whereas esterification of lipid (based on the absence of change in circulating NEFA levels) and export of lipids (based on induction of ApoB and Mttp genes) from liver should not be altered. The induction of de novo lipogenesis is in agreement with the activation of both PERK and IRE1 branches of the unfolded protein response in the liver of CypD-KO mice, as both pathways were shown to activate the lipogenic transcription factor SREBP-1c [25][26][27]. Particularly, accumulation of DAG likely contributes to PKCε activation in the liver of CypD-KO mice.…”

Section: Discussionsupporting

confidence: 68%

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 68%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Diet-induced NALFD might stimulate a feed-forward loop exacerbating DNL and ectopic lipid deposition. For example, fructose-fed hamsters have hypertriglyceridaemia, NAFLD and insulin resistance associated with increased DNL 61 , and because fructose inhibits fatty-acid oxidation both directly and indirectly, excess fructose intake is likely to stimulate DNL and hepatic insulin resistance 62,63 . However, reducing lipogenic gene expression by knockdown of the upstream gene encoding peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) 64 protects against fructose-induced hepatic insulin resistance 65 .…”

Section: Regulation Of Hepatic Lipid Synthesismentioning

confidence: 99%

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Perry

Samuel

Petersen

et al. 2014

Nature

946

738

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.

show abstract

“…Strikingly, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a key regulator of SREBP-1 expression, activates ER stress to promote hepatic IR and lipid accumulation [23]. Additional mechanisms involved in SREBP-1c activation by ER stress include rapid degradation of its upstream inhibitor insulin-induced gene 1 (Insig1) [26] and direct transcriptional activation of the SREBP-1c gene by the IRE-1a-XBP1 pathway [27]. Of note, XBP1 is also capable of enhancing the degradation of lipogenic mRNAs through a SREBP-1c-independent mechanism, in a process known as regulated IRE-1-dependent decay (RIDD, Box 1) [28].…”

Section: Box 2 Interplay Between Inflammatory Pathways and Er Stressmentioning

confidence: 99%

Targeting endoplasmic reticulum stress in insulin resistance

Salvadó

Palomer

Barroso

et al. 2015

Trends in Endocrinology & Metabolism

188

150

View full text Add to dashboard Cite

Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice

Cited by 93 publications

References 32 publications

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

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

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Targeting endoplasmic reticulum stress in insulin resistance

Contact Info

Product

Resources

About