Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress

Yamamoto, Keisuke; Takahara, Kazuna; Oyadomari, Seiichi; Okada, Tetsuya; Satō, Takashi; Harada, Akira; Mori, Kazutoshi

doi:10.1091/mbc.e09-02-0133

Cited by 266 publications

(265 citation statements)

References 62 publications

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“…Although Atf6α −/− mice display no apparent developmental phenotype under normal growth conditions, Atf6α deletion severely impairs liver function and prolongs steatosis compared with wild-type mice upon ER stress (Wu et al 2007;Rutkowski et al 2008;Yamamoto et al 2010). This might result from prolonged CHOP expression in response to chronic UPR activation and consequent suppression of C/EBPα (Rutkowski et al 2008) as well as reduced expression of chaperones and ERAD functions (Wu et al 2007;Yamamoto et al 2010). On the other hand, forced expression of the functionally active nuclear fragment of ATF6 in zebrafish causes fatty liver (Howarth et al 2014), suggesting that fine-tuning of ATF6α may be important to prevent liver steatosis.…”

Section: Atf6αmentioning

confidence: 99%

“…First, the expression levels of TFs need to be properly regulated at the appropriate level. For example, the absence of ATF6α causes liver steatosis upon ER stress (Wu et al 2007;Rutkowski et al 2008;Yamamoto et al 2010), whereas overexpression of the active form of ATF6α in zebrafish livers causes fatty liver due to lipid accumulation (Howarth et al 2014). There appears to be an optimum of expression versus toxicity.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Section: Atf6αmentioning

confidence: 99%

Section: Therapeutic Implicationsmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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“…Mice impaired in UPR signaling or with an intact UPR but compromised ER protein folding developed profound hepatic steatosis upon challenge with the ER stress-inducing agent tunicamycin (TM) (23,24). This steatosis was accompanied by prolonged suppression of the expression of a host of metabolic genes.…”

Section: Atf4mentioning

confidence: 99%

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Chikka

McCabe

Tyra

et al. 2013

Journal of Biological Chemistry

100

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Background: ER stress regulates metabolic gene expression in liver. Results: The ER stress-regulated pro-apoptotic transcription factor CHOP binds to the promoters of metabolic genes and is necessary for their suppression. Conclusion: CHOP contributes to the metabolic alterations that accompany ER stress in vivo. Significance: These findings suggest that CHOP has a non-apoptotic role in regulating metabolic physiology.

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“…This seems likely due to the induction of glucose-dependent XBP-1s in addition to ER stress (29). Previous KO gene studies showed that the absence of ER stress-sensing proteins, including ATF6a, caused hepatic steatosis (30,31). It was also reported that ER stress-induced hepatic steatosis was alleviated by the administration of recombinant FGF21 protein (9).…”

Section: Discussionmentioning

confidence: 97%

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress

Cited by 266 publications

References 62 publications

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Physiological/pathological ramifications of transcription factors in the unfolded protein response

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

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