Upregulation of apolipoprotein B secretion, but not lipid, by tumor necrosis factor-alpha in rat hepatocyte cultures in the absence of extracellular fatty acids.
Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the host response to infection. Rapidly liberated to the bloodstream, TNF-alpha triggers the production of other cytokines and the acute-phase response. Hypertriglyceridemia is a sepsis hallmark associated with high plasma levels of very low-density lipoprotein (VLDL) particles, partly ascribed to increased hepatic production. The kinetics of the hepatocyte response, the cytokine/s responsible, and the underlying mechanisms are not fully elucidated. VLDL biogenesis is a complex, time-consuming process that depends on lipid availability and microsomal triglyceride transfer protein (MTP) activity for correct apolipoprotein B (apoB) lipidation. Studies were performed to define the direct effect of TNF-alpha on VLDL secretion rate and composition in rat hepatocytes cultured in conditions resembling the fed situation. Increases of 17-24% in the number of VLDL particles secreted and of 44-88% in the cellular levels of apoB mRNA were caused by 5, 20, or 100 ng/mL TNF-alpha in 8 h. Lipoprotein secretion returned to baseline levels in 16 h, whereas TNF-alpha-treated cells continued to exhibit higher apoB transcript levels. The mass of each lipid class in secreted VLDL and of MTP mRNA in cells was not affected by any of the tested TNF-alpha doses or treatment periods. These findings indicate that over a wide range of concentrations, TNF-alpha was capable of inducing sustained upregulation of apoB mRNA expression and transient increase in secretion of its protein, but, apparently, VLDL triglyceride secretion was not a TNF-alpha target under conditions in which fatty acids were not extracellularly provided.
Bartolomé
Nerea
N
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Sarriena s/n, 48940-Leioa, Spain.
Rodríguez
Lorena
L
Martínez
María J
MJ
Ochoa
Begoña
B
Chico
Yolanda
Y
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008074:Lipoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D001055:Apolipoproteins B; D002352:Carrier Proteins; D005227:Fatty Acids; D008055:Lipids; D008074:Lipoproteins; D012333:RNA, Messenger; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C106092:microsomal triglyceride transfer protein