Links between enhanced fatty acid flux, protein kinase C and NFkappaB activation, and apoB-lipoprotein production in the fructose-fed hamster model of insulin resistance.
In the current study, we show evidence, in a fructose-fed hamster model of insulin resistance, that free fatty acid (FFA) can induce hepatic insulin resistance in part via PKC activation leading to increased production of atherogenic apoB100-containing lipoproteins. Interestingly, IkappaB-kinase beta (IKKbeta)-dependent NF-kappaB was activated in hepatocytes from the fructose-fed hamster as an indication for PKC activation. Treatment of hepatocytes with oleate for 16h showed the activation of the PKC isoforms, PKCalpha/betaII, in a dose dependent manner. Strikingly, the general PKC inhibitor, bisindolylmaleimide-I, Bis-I (5 microM) was found to ameliorate fructose-induced insulin resistance, restoring the phosphorylation status of PKB and suppressing apoB100 overproduction in ex vivo and in vivo. The data suggest that hepatic PKC activation, induced by increased circulating FFA may be an important factor in the development of insulin resistance and dyslipidemia seen in the fructose-fed hamster model.
Ragheb
Rafik
R
Department of Biochemistry, Faculty of Science, University of Ain Shams, Abbasia Square, Cairo 11566, Egypt. rafik.ragheb@utoronto.ca
Medhat
Amina M
AM
Shanab
Gamila M L
GM
Seoudi
Dina M
DM
Fantus
I G
IG
D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005632:Fructose / Q000008:administration & dosage; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006951:Hyperlipoproteinemias / Q000209:etiology* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008647:Mesocricetus; D016328:NF-kappa B / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D053299:Apolipoprotein B-100; D005230:Fatty Acids, Nonesterified; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019301:Oleic Acid; D005632:Fructose; D011493:Protein Kinase C; C070515:bisindolylmaleimide I