XBP1s Is an Anti-lipogenic Protein.
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.
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, hilde.herrema@childrens.harvard.edu.
Hilde
H
Herrema
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Yingjiang
Y
Zhou
the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, and.
Dongyan
D
Zhang
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Justin
J
Lee
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Mario Andres
MA
Salazar Hernandez
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.
Gerald I
GI
Shulman
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, umut.ozcan@childrens.harvard.edu.
Umut
U
Ozcan
D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon
endoplasmic reticulum stress (ER stress); insulin resistance; liver; obesity; unfolded protein response (UPR)