p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis

Lee, Jaemin; Sun, Cheng; Zhou, Yang; Lee, Justin; Gökalp, Deniz; Herrema, Hilde; Park, Sang Won; Davis, Roger J.; Özcan, Umut

doi:10.1038/nm.2449

Cited by 184 publications

(180 citation statements)

References 50 publications

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“…6A) but not at 3 months of age (data not shown). When ER stress was induced by 1-h refeeding after the 24-h fasting period, according to a previously reported ER stress paradigm (30), abnormal increases in the phosphorylation of IRE1a (Fig. 6B) and JNK (Fig.…”

Section: Orexin-induced Daily Glucose Rhythm Prevents Er Stress and Hsupporting

confidence: 58%

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

et al. 2014

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Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wildtype mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.Maintaining glucose and energy homeostasis throughout the day is essential for survival. Therefore, different metabolic functions are timely activated according to the circadian rhythm. Recently, it has also become clear that fine tuning of daily metabolic rhythms is crucial for preventing metabolic abnormalities. For instance, chronic disruption of circadian rhythm in humans, as seen in shift workers, increases the risk of obesity and type 2 diabetes (1,2), and circadian rhythms of glucose regulation are impaired in diabetic animals and patients with diabetes (3).Circadian rhythms of peripheral tissues, including liver, are entrained to the central biological clock located in the suprachiasmatic nuclei (SCN) via autonomic and hormonal pathways (4). The liver plays a pivotal role in maintaining optimal glucose levels via hepatic glucose production (HGP) and glucose uptake. The daily rhythm of HGP is regulated by the autonomic nervous system under SCN control, leading to generation of a daily rhythm in basal blood glucose levels independently of the feeding rhythm (5). The central clock is also crucial for preventing metabolic abnormalities

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Section: Orexin-induced Daily Glucose Rhythm Prevents Er Stress and Hsupporting

confidence: 58%

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

et al. 2014

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“…It also has yet to be dissected how XBP1s can be delicately regulated in vivo to control different sets of gene expression programs under these circumstances. It warrants further investigation whether XBP1s may act as a molecular regulatory switch through acetylation 37 , phosphorylation 15 or other modifications under anabolic versus catabolic conditions. In summary, our findings indicate that hepatic IRE1a serves as a crucial component of the nutrient-sensing machinery that regulates the metabolic adaptive response to starvation.…”

Section: Xbp1s Normalizes the Metabolic Impairment Inmentioning

confidence: 99%

“…Studies in animal models have implicated IRE1a or XBP1s in both glucose and lipid metabolism 6,8,9,[13][14][15][16][17][18][19][20] . Recently, it was shown that the hepatic IRE1a-XBP1 pathway is activated upon refeeding, and overexpression of XBP1s in livers of mice may promote postprandial metabolic changes 6 .…”

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confidence: 99%

“…Recently, it was shown that the hepatic IRE1a-XBP1 pathway is activated upon refeeding, and overexpression of XBP1s in livers of mice may promote postprandial metabolic changes 6 . Hepatic overexpression of XBP1s was also reported to exert a suppressive effect upon gluconeogenesis 15,20 . In addition, the hepatic IRE1a-XBP1 pathway was shown to play a crucial role in the assembly of very low-density lipoprotein (VLDL) and hepatic lipid homoeostasis through regulation of protein disulphide isomerase expression 18 .…”

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confidence: 99%

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Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

et al. 2014

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Although the mammalian IRE1a-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1a signalling in vivo remains poorly understood. Here we show that hepatic IRE1a functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1a-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1a results in impairment of fatty acid b-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1a null mice. XBP1s directly binds to and activates the promoter of PPARa, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1a promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial b-oxidation and ketogenesis through the XBP1s-PPARa axis.

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“…Reinstating the hepatic activity of XBP1s reduced ER stress and improved glucose homeostasis through mechanisms that are both dependent (14,15) and independent of XBP1s transcriptional activity (16). This indicates that XBP1s is indispensable for the maintenance of glucose homeostasis in obesity.…”

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confidence: 91%

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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p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis

Cited by 184 publications

References 50 publications

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

XBP1s Is an Anti-lipogenic Protein

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