Induction of liver steatosis and lipid droplet formation in ATF6α-knockout mice burdened with pharmacological endoplasmic reticulum stress

Keisuke Yamamoto, Kazuna Takahara, Seiichi Oyadomari, Tetsuya Okada, Takashi Sato, Akihiro Harada, Kazutoshi Mori

Research output: Contribution to journalArticlepeer-review

236 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2975-2986
Number of pages12
JournalMolecular Biology of the Cell
Volume21
Issue number17
DOIs
StatePublished - 1 Sep 2010
Externally publishedYes

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