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J Biol Chem. 2016 Aug 12;291(33):17394-404. doi: 10.1074/jbc.M116.728949. Epub 2016 Jun 20.

XBP1s Is an Anti-lipogenic Protein.

Author information

1
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, hilde.herrema@childrens.harvard.edu.
2
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
3
the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, and.
4
the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520.
5
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, umut.ozcan@childrens.harvard.edu.

Abstract

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 diet-induced obese and genetically obese and insulin-resistant ob/ob mice. Furthermore, we also show that PKCϵ 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.

KEYWORDS:

endoplasmic reticulum stress (ER stress); insulin resistance; liver; obesity; unfolded protein response (UPR)

PMID:
27325692
PMCID:
PMC5016136
DOI:
10.1074/jbc.M116.728949
[Indexed for MEDLINE]
Free PMC Article

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