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

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6α plays a pivotal role in transcriptional in...

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Autores principales: Yamamoto, Keisuke, Takahara, Kazuna, Oyadomari, Seiichi, Okada, Tetsuya, Sato, Takashi, Harada, Akihiro, Mori, Kazutoshi
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929991/
https://www.ncbi.nlm.nih.gov/pubmed/20631254
http://dx.doi.org/10.1091/mbc.E09-02-0133
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author Yamamoto, Keisuke
Takahara, Kazuna
Oyadomari, Seiichi
Okada, Tetsuya
Sato, Takashi
Harada, Akihiro
Mori, Kazutoshi
author_facet Yamamoto, Keisuke
Takahara, Kazuna
Oyadomari, Seiichi
Okada, Tetsuya
Sato, Takashi
Harada, Akihiro
Mori, Kazutoshi
author_sort Yamamoto, Keisuke
collection PubMed
description Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6α plays a pivotal role in transcriptional induction of ER-localized molecular chaperones and folding enzymes as well as components of ER-associated degradation, and thereby mouse embryonic fibroblasts deficient in ATF6α are sensitive to ER stress. However, ATF6α-knockout mice show no apparent phenotype under normal growing conditions. In this report, we burdened mice with intraperitoneal injection of the ER stress-inducing reagent tunicamycin and found that wild-type mice were able to recover from the insult, whereas ATF6α-knockout mice exhibited liver dysfunction and steatosis. Thus, ATF6α-knockout mice accumulated neutral lipids in the liver such as triacylglycerol and cholesterol, which was ascribable to blockage of β-oxidation of fatty acids caused by decreased mRNA levels of the enzymes involved in the process, suppression of very-low-density lipoprotein formation due to destabilized apolipoprotein B-100, and stimulation of lipid droplet formation resulting from transcriptional induction of adipose differentiation-related protein. Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis.
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spelling pubmed-29299912010-11-16 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 Sato, Takashi Harada, Akihiro Mori, Kazutoshi Mol Biol Cell Articles Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6α plays a pivotal role in transcriptional induction of ER-localized molecular chaperones and folding enzymes as well as components of ER-associated degradation, and thereby mouse embryonic fibroblasts deficient in ATF6α are sensitive to ER stress. However, ATF6α-knockout mice show no apparent phenotype under normal growing conditions. In this report, we burdened mice with intraperitoneal injection of the ER stress-inducing reagent tunicamycin and found that wild-type mice were able to recover from the insult, whereas ATF6α-knockout mice exhibited liver dysfunction and steatosis. Thus, ATF6α-knockout mice accumulated neutral lipids in the liver such as triacylglycerol and cholesterol, which was ascribable to blockage of β-oxidation of fatty acids caused by decreased mRNA levels of the enzymes involved in the process, suppression of very-low-density lipoprotein formation due to destabilized apolipoprotein B-100, and stimulation of lipid droplet formation resulting from transcriptional induction of adipose differentiation-related protein. Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis. The American Society for Cell Biology 2010-09-01 /pmc/articles/PMC2929991/ /pubmed/20631254 http://dx.doi.org/10.1091/mbc.E09-02-0133 Text en © 2010 by The American Society for Cell Biology This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
spellingShingle Articles
Yamamoto, Keisuke
Takahara, Kazuna
Oyadomari, Seiichi
Okada, Tetsuya
Sato, Takashi
Harada, Akihiro
Mori, Kazutoshi
Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title_full Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title_fullStr Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title_full_unstemmed Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title_short Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress
title_sort induction of liver steatosis and lipid droplet formation in atf6α-knockout mice burdened with pharmacological endoplasmic reticulum stress
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929991/
https://www.ncbi.nlm.nih.gov/pubmed/20631254
http://dx.doi.org/10.1091/mbc.E09-02-0133
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