iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation

<b>Background:</b> Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β<sup>−/−</sup> mice fed with a methionine-choline-deficient diet (MCD)...

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Main Authors:	Yanan Ming, Xingya Zhu, Sabine Tuma-Kellner, Alexandra Ganzha, Gerhard Liebisch, Hongying Gan-Schreier, Walee Chamulitrat
Format:	Article
Language:	English
Published:	MDPI AG 2019-08-01
Series:	Cells
Subjects:	PLA2G6 endoplasmic reticulum phospholipids bile acids lean NASH unfolded protein response
Online Access:	https://www.mdpi.com/2073-4409/8/8/879

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spelling	doaj-43a9497e88a84b07bdd7d16a2ef3b1f52020-11-24T21:21:02ZengMDPI AGCells2073-44092019-08-018887910.3390/cells8080879cells8080879iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell ProliferationYanan Ming0Xingya Zhu1Sabine Tuma-Kellner2Alexandra Ganzha3Gerhard Liebisch4Hongying Gan-Schreier5Walee Chamulitrat6Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, GermanyDepartment of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany<b>Background:</b> Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β<sup>−/−</sup> mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). <b>Methods:</b> Female WT (wild-type) and iPla2β<sup>−/−</sup> mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. <b>Results:</b> MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. <b>Conclusion:</b> iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.https://www.mdpi.com/2073-4409/8/8/879PLA2G6endoplasmic reticulumphospholipidsbile acidslean NASHunfolded protein response
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Yanan Ming Xingya Zhu Sabine Tuma-Kellner Alexandra Ganzha Gerhard Liebisch Hongying Gan-Schreier Walee Chamulitrat
spellingShingle	Yanan Ming Xingya Zhu Sabine Tuma-Kellner Alexandra Ganzha Gerhard Liebisch Hongying Gan-Schreier Walee Chamulitrat iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation Cells PLA2G6 endoplasmic reticulum phospholipids bile acids lean NASH unfolded protein response
author_facet	Yanan Ming Xingya Zhu Sabine Tuma-Kellner Alexandra Ganzha Gerhard Liebisch Hongying Gan-Schreier Walee Chamulitrat
author_sort	Yanan Ming
title	iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation
title_short	iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation
title_full	iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation
title_fullStr	iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation
title_full_unstemmed	iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation
title_sort	ipla2β deficiency suppresses hepatic er upr, fxr, and phospholipids in mice fed with mcd diet, resulting in exacerbated hepatic bile acids and biliary cell proliferation
publisher	MDPI AG
series	Cells
issn	2073-4409
publishDate	2019-08-01
description	<b>Background:</b> Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β<sup>−/−</sup> mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). <b>Methods:</b> Female WT (wild-type) and iPla2β<sup>−/−</sup> mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. <b>Results:</b> MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. <b>Conclusion:</b> iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.
topic	PLA2G6 endoplasmic reticulum phospholipids bile acids lean NASH unfolded protein response
url	https://www.mdpi.com/2073-4409/8/8/879
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iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation

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