Inflammatory NF-κB activation promotes hepatic apolipoprotein B100 secretion: Evidence for a link between hepatic inflammation and lipoprotein production

Julie Tsai, Rianna Zhang, Wei Qiu, Qiaozhu Su, Mark Naples, Khosrow Adeli

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-κB (NF-κB) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IκB (inhibitor of NF-κB) level, indicating activation of the inflammatory NF-κB cascade. Importantly, IKK (IκB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-κB has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-κB pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-κB pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-κB signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.

Original languageEnglish (US)
Pages (from-to)G1287-G1298
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 1 2009

Fingerprint

Apolipoproteins
Lipoproteins
Inflammation
Liver
Cricetinae
Insulin
Fructose
Hepatocytes
Metabolome
Protein Stability
Hypertriglyceridemia
Hep G2 Cells
Protein Biosynthesis
Insulin Resistance
Phosphotransferases
Animal Models
Cell Culture Techniques

Keywords

  • Cholesterol
  • Fructose
  • Hamster
  • Insulin resistance
  • Proteasomal degradation
  • Translation
  • Triglycerides

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Inflammatory NF-κB activation promotes hepatic apolipoprotein B100 secretion : Evidence for a link between hepatic inflammation and lipoprotein production. / Tsai, Julie; Zhang, Rianna; Qiu, Wei; Su, Qiaozhu; Naples, Mark; Adeli, Khosrow.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 6, 01.06.2009, p. G1287-G1298.

Research output: Contribution to journalArticle

@article{a84857b7059e4a8aa8a763a3ca556dcd,
title = "Inflammatory NF-κB activation promotes hepatic apolipoprotein B100 secretion: Evidence for a link between hepatic inflammation and lipoprotein production",
abstract = "Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-κB (NF-κB) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IκB (inhibitor of NF-κB) level, indicating activation of the inflammatory NF-κB cascade. Importantly, IKK (IκB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-κB has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-κB pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-κB pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-κB signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.",
keywords = "Cholesterol, Fructose, Hamster, Insulin resistance, Proteasomal degradation, Translation, Triglycerides",
author = "Julie Tsai and Rianna Zhang and Wei Qiu and Qiaozhu Su and Mark Naples and Khosrow Adeli",
year = "2009",
month = "6",
day = "1",
doi = "10.1152/ajpgi.90540.2008",
language = "English (US)",
volume = "296",
pages = "G1287--G1298",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Inflammatory NF-κB activation promotes hepatic apolipoprotein B100 secretion

T2 - Evidence for a link between hepatic inflammation and lipoprotein production

AU - Tsai, Julie

AU - Zhang, Rianna

AU - Qiu, Wei

AU - Su, Qiaozhu

AU - Naples, Mark

AU - Adeli, Khosrow

PY - 2009/6/1

Y1 - 2009/6/1

N2 - Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-κB (NF-κB) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IκB (inhibitor of NF-κB) level, indicating activation of the inflammatory NF-κB cascade. Importantly, IKK (IκB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-κB has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-κB pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-κB pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-κB signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.

AB - Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-κB (NF-κB) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IκB (inhibitor of NF-κB) level, indicating activation of the inflammatory NF-κB cascade. Importantly, IKK (IκB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-κB has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-κB pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-κB pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-κB signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.

KW - Cholesterol

KW - Fructose

KW - Hamster

KW - Insulin resistance

KW - Proteasomal degradation

KW - Translation

KW - Triglycerides

UR - http://www.scopus.com/inward/record.url?scp=67049134412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67049134412&partnerID=8YFLogxK

U2 - 10.1152/ajpgi.90540.2008

DO - 10.1152/ajpgi.90540.2008

M3 - Article

C2 - 19342510

AN - SCOPUS:67049134412

VL - 296

SP - G1287-G1298

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 6

ER -