Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress

Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of sev...

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Published in:	International journal of molecular sciences Vol. 21; no. 19; p. 7097
Main Authors:	Rennert, Christiane, Heil, Theresa, Schicht, Gerda, Stilkerich, Anna, Seidemann, Lena, Kegel-Hübner, Victoria, Seehofer, Daniel, Damm, Georg
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-10-2020 MDPI
Subjects:	Accumulation Adult Aged Apoptosis Autophagy Body weight Cells, Cultured Endoplasmic reticulum Endoplasmic Reticulum Stress Enzymes ER stress Fatty Acids, Nonesterified - metabolism Fatty liver Female Health aspects Hepatocytes Hepatocytes - metabolism Homeostasis Humans Kinases Lipid Metabolism Lipid peroxidation Lipids Liver Liver diseases Male Middle Aged NAFLD NASH Non-alcoholic Fatty Liver Disease - metabolism Observations Oxidation Oxidative Stress primary human hepatocytes Proteins Steatosis Germany NAFLD liver primary human hepatocytes ER stress NASH steatosis oxidative stress
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Summary:	Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms21197097