Abstract
Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β−/− 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). Methods: Female WT (wild-type) and iPla2β−/− 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. Results: 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. Conclusion: 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, which describes a spectrum of steatosis, non-alcoholic steatohepatitis (NASH) to cirrhosis, which may progress to primary liver cancer
We have shown that iPla2β deficiency in the intestine elicits a suppressive effect on an endoplasmic reticulum (ER) unfolded protein response (UPR) protein X-box binding protein-1 (Xbp-1) [20]
We provided molecular mechanisms for the effects of iPla2β inactivation during methionine-choline-deficient diet (MCD)-induced lean NASH [16] involving alterations of ER PL and downregulation of homeostatic genes, which led to an increase of bile acids (BA) and potentially biliary liver disease
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, which describes a spectrum of steatosis, non-alcoholic steatohepatitis (NASH) to cirrhosis, which may progress to primary liver cancer. Mice are, not protected from hepatic steatosis and, on the other hand, show exaggerated hepatic fibrosis with hepatic stellate cell activation [16] This indicates an opposing role of iPla2β inactivation between obese NAFLD and lean NASH models. It has been shown that hepatic endoplasmic reticulum (ER) stress plays a significant role in the pathogenesis of obese NAFLD [18], but not of MCD-induced lean NASH [19]. We provided molecular mechanisms for the effects of iPla2β inactivation during MCD-induced lean NASH [16] involving alterations of ER PL and downregulation of homeostatic genes, which led to an increase of BA and potentially biliary liver disease
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