Kupffer cell products and interleukin 1beta directly promote VLDL secretion and apoB mRNA up-regulation in rodent hepatocytes.
Plasma VLDL accumulation in Gram-negative sepsis is partly ascribed to an increased hepatic VLDL production driven by pro-inflammatory cytokines. We previously showed that hepatocytes of the Kupffer cell (KC)-rich periportal area are major contributors to enhanced VLDL production in lipopolysaccharide (LPS)-injected rats. However, it remains to be established whether KC generated products directly affect the number (apoB) and composition of secreted VLDL. Using rat primary cells, we show here that hepatocytes respond to stimulation by soluble mediators released by LPS-stimulated Kupffer cells with enhanced secretion of apoB and triglycerides in phospholipid-rich VLDL particles. Unstimulated KC products also augmented the secretion of normal VLDL, doubling apoB mRNA abundance. IL-1beta treatment resulted in concentration-dependent increases of hepatocyte apoB mRNA and protein secretion, increases that were greater, but not additive, when combined with IL-6 and TNF-alpha. Lipid secretion and MTP mRNA levels were unaffected by cytokines. In summary: (i) enhanced secretion of phospholipid-rich VLDL particles is a net hepatocyte response to LPS-stimulated KC products, which gives a clue about the local role of Kupffer cells in septic dyslipidemia induction; and (ii) pro-inflammatory cytokines act redundantly to enhance apoB secretion involving translational apoB up-regulation, but other humoral components or KC mediators are necessary to accomplish increased lipid association.
Bartolomé
Nerea
N
Department of Physiology, Faculty of Medicine, University of the Basque Country, Leioa, Spain.
Arteta
Beatriz
B
Martínez
María José
MJ
Chico
Yolanda
Y
Ochoa
Begoña
B
D000818:Animals; D053299:Apolipoprotein B-100 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D018929:Cell Culture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D019446:Endotoxemia; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008079:Lipoproteins, VLDL / Q000819:agonists / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D053299:Apolipoprotein B-100; D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011994:Recombinant Proteins