Gruenig 2020 Biochem Pharmacol
|Grünig D, Szabo L, Marbet M, Krähenbühl S (2020) Valproic acid affects fatty acid and triglyceride metabolism in HepaRG cells exposed to fatty acids by different mechanisms. Biochem Pharmacol 177:113860.|
Abstract: Treatment with valproate is associated with hepatic steatosis, but the mechanisms are not fully elucidated in human cell systems. We therefore investigated the effects of valproate on fatty acid and triglyceride metabolism in HepaRG cells, a human hepatoma cell line. In previously fatty acid loaded HepaRG cells, valproate impaired lipid droplet disposal starting at 1 mM after incubation for 3 or 7 days. Valproate increased the expression of genes associated with fatty acid import and triglyceride synthesis, but did not relevantly affect expression of genes engaged in fatty acid activation. Valproate impaired mitochondrial fatty acid metabolism by inhibiting β-ketothiolase and the function of the electron transport chain, which was associated with increased mitochondrial reactive oxygen species production. Valproate increased the mitochondrial DNA copy number per HepaRG cell, possibly as a consequence of impaired mitochondrial function. Valproate decreased the hepatocellular mRNA and protein expression of the fatty acid binding protein 1 (FABP1) and of the microsomal triglyceride transfer protein (MTTP) at 1 mM and increased the hepatocellular concentration of free fatty acids. Furthermore, valproate decreased protein expression and excretion of ApoB100 in HepaRG cells at 1 mM, reflecting impaired formation and excretion of very low-density lipoprotein (VLDL). In conclusion, valproate increased the hepatocellular triglyceride content by multiple mechanisms, whereby impaired expression of FABP1 and MTTP as well as impaired VLDL formation and excretion appeared to be dominant. Valproate caused cell death mainly by apoptosis, which may be a consequence of mitochondrial oxidative stress and increased hepatocellular concentration of free fatty acids.
Copyright © 2020 Elsevier Inc. All rights reserved.
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria
Regulation: Fatty acid Coupling state: LEAK, OXPHOS, ET Pathway: N, S, DQ, CIV, ROX HRR: Oxygraph-2k