GRP78 expression inhibits insulin and ER stress–induced SREBP-1c activation and reduces hepatic steatosis in mice

Kammoun, Hélène L.; Chabanon, Hervé; Hainault, Isabelle; Luquet, Serge; Magnan, Christophe; Koike, Takao; Ferré, Pascal; Foufelle, Fabienne

doi:10.1172/jci37007

Cited by 636 publications

(573 citation statements)

References 59 publications

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“…24 Gene knockdown of GRP78 has been demonstrated to block ER stress-induced autophagosome formation in human cells. 24,51 These results are in line with our finding that treatment with siGRP78 attenuated the augmented expression of LC3-II in RVLM of SHR. Together with our finding of an involvement of ER stress-associated autophagy in hypertension phenotype of SHR, it is conceivable that under the scenario of chronic ER stress, as in RVLM of SHR, ER stress-associated autophagy might play a predominant role in the pathogenesis of hypertension.…”

Section: Discussionsupporting

confidence: 87%

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

2013

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Abstract-Perturbations of proper functions of the endoplasmic reticulum (ER) cause accumulation of misfolded or unfolded proteins in the cell, creating a condition known as ER stress. Prolonged ER stress has been implicated in hypertension. Oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside, plays a pivotal role in neurogenic hypertension. This study aimed to evaluate the contribution of ER stress in RVLM to oxidative stress-associated hypertension and delineate the underlying molecular mechanisms. The expression of glucose-regulated protein 78 kDa and the phosphorylation of protein kinase RNA-like ER kinase-translation initiation factor α, 2 major protein markers of ER stress, were augmented in RVLM and preceded the development of hypertensive phenotype in spontaneously hypertensive rats. In RVLM of spontaneously hypertensive rats, stabilizing ER stress by salubrinal promoted antihypertension, and scavenging the reactive oxygen species by tempol reduced the augmented ER stress. Furthermore, induction of oxidative stress by angiotensin II induced ER stress in RVLM, and induction of ER stress by tunicamycin in RVLM induced pressor response in normotensive Wistar-Kyoto rats. Autophagy, as reflected by the expression of lysosome-associated membrane protein-2 and microtubule-associated protein 1 light chain 3-II (LC3-II), was significantly increased in RVLM of spontaneously hypertensive rats and was abrogated by salubrinal. In addition, inhibition of autophagy or silencing LC3-II gene in RVLM resulted in antihypertension in spontaneously hypertensive rats. These results suggest that redox-sensitive induction of ER stress and activation of autophagy in RVLM contribute to oxidative stress-

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Section: Discussionsupporting

confidence: 87%

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

2013

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“…Despite a modest association between TRIB3 transcripts and transcripts encoding SREBP-1c, recent studies have shown that nuclear import of SREBP-1c is enhanced by endoplasmic reticulum stress, which is implicated in insulin resistance [12]. We therefore directly determined effects of SREBP-1c and PPARGC1B on transcriptional regulation of the human TRIB3 gene, in co-transfection experiments using HepG2 cells.…”

Section: Resultsmentioning

confidence: 99%

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

et al. 2010

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Aims/hypothesis The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulinmediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3. Methods We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance. ResultsIn our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p=0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p=0.0014) and mRNA expression of PPARGC1A (p=0.0020), PPARGC1B (p<0.0001), USF1 (p=0.0017), FOXO1 (p=0.0003) and SREBP-1c (also known as SREBF1; p=0.0360). Furthermore ligands of peroxisome proliferator-activated receptor α/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells. Conclusions/interpretation We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.

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“…Upregulation of Srebp‐1c expression was found in the liver of obese mice (Ferré & Foufelle, 2010; Kammoun et al ., 2009). Liver‐specific Srebp‐1c transgenic mice showed hepatic steatosis (Knebel et al ., 2012), suggesting that Srebp‐1c was responsible for the pathogenesis of this condition.…”

Section: Discussionmentioning

confidence: 99%

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

et al. 2017

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SummaryCaloric restriction (CR) can delay onset of several age‐related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR‐associated metabolic remodeling of WAT remain unclear. Sterol regulatory element‐binding protein‐1c (Srebp‐1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp‐1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α (Pgc‐1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp‐1c, most of these CR‐associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp‐1c may be an important factor both for CR‐associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp‐1c, the primary FA biosynthesis‐promoting transcriptional factor implicated in fatty liver disease, is also the food shortage‐responsive factor in WAT. This indicated that Srebp‐1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

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GRP78 expression inhibits insulin and ER stress–induced SREBP-1c activation and reduces hepatic steatosis in mice

Cited by 636 publications

References 59 publications

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

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