Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum
Open Access
- 18 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death Discovery
- Vol. 6 (1), 1-16
- https://doi.org/10.1038/s41420-020-0241-z
Abstract
Genetic obesity increases in liver phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio, inducing endoplasmic reticulum (ER) stress without concomitant increase of ER chaperones. Here, it is found that exposing mice to a palm oil-based high fat (HF) diet induced obesity, loss of liver PE, and loss of the ER chaperone Grp78/BiP in pericentral hepatocytes. In Hepa1-6 cells treated with elevated concentration of palmitate to model lipid stress, Grp78/BiP mRNA was increased, indicating onset of stress-induced Unfolded Protein Response (UPR), but Grp78/BiP protein abundance was nevertheless decreased. Exposure to elevated palmitate also induced in hepatoma cells decreased membrane glycosylation, nuclear translocation of pro-apoptotic C/EBP-homologous-protein-10 (CHOP), expansion of ER-derived quality control compartment (ERQC), loss of mitochondrial membrane potential (MMP), and decreased oxidative phosphorylation. When PE was delivered to Hepa1-6 cells exposed to elevated palmitate, effects by elevated palmitate to decrease Grp78/BiP protein abundance and suppress membrane glycosylation were blunted. Delivery of PE to Hepa1-6 cells treated with elevated palmitate also blunted expansion of ERQC, decreased nuclear translocation of CHOP and lowered abundance of reactive oxygen species (ROS). Instead, delivery of the chemical chaperone 4-phenyl-butyrate (PBA) to Hepa1-6 cells treated with elevated palmitate, while increasing abundance of Grp78/BiP protein and restoring membrane glycosylation, also increased ERQC, expression and nuclear translocation of CHOP, non-mitochondrial oxygen consumption, and generation of ROS. Data indicate that delivery of PE to hepatoma cells under lipid stress recovers cell function by targeting the secretory pathway and by blunting pro-apoptotic branches of the UPR.Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (R01-DK102206, 3R01DK102206-02S1, UL1TR000039, 5R25GM083247-0)
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
This publication has 54 references indexed in Scilit:
- Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to TherapyTrends in Cell Biology, 2017
- Determinants and Consequences of ObesityAmerican Journal of Public Health, 2016
- The Hunger Genes: Pathways to ObesityCell, 2015
- The Problem of Establishing Relationships between Hepatic Steatosis and Hepatic Insulin ResistanceCell Metabolism, 2012
- Endoplasmic reticulum stress, obesity and diabetesTrends in Molecular Medicine, 2011
- Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesityNature, 2011
- As a Matter of FatCell Metabolism, 2009
- Signal integration in the endoplasmic reticulum unfolded protein responseNature Reviews Molecular Cell Biology, 2007
- Dietary Fat and Weight Gain Among Women in the Nurses’ Health StudyObesity, 2007
- Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle-aged womenThe American Journal of Clinical Nutrition, 2003