Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver.
To study mechanisms by which free fatty acids (FFAs) cause hepatic insulin resistance, we have used euglycemic-hyperinsulinemic clamping with and without infusion of lipid/heparin (to raise or to lower plasma FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (+210%), increased activities of two serine/threonine kinases (protein kinase C-delta and inhibitor of kappaB [IkappaB] kinase-beta), increased activation of the proinflammatory nuclear factor-kappaB (NF-kappaB) pathway (IkappaB kinase-beta, +640%; IkappaB-alpha, -54%; and NF-kappaB, +73%), and increased expression of inflammatory cytokines (tumor necrosis factor-alpha, +1,700% and interleukin-1beta, +440%) and plasma levels of monocyte chemoattractant protein-1 (+220%). We conclude that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis.
Boden
Guenther
G
Division of Endocrinology, Diabetes, and Metabolism, Temple University School of Medicine, 3401 North Broad St., Philadelphia, Pennsylvania 19140, USA. bodengh@tuhs.temple.edu
She
Pengxiang
P
Mozzoli
Maria
M
Cheung
Peter
P
Gumireddy
Kiranmai
K
Reddy
Prekumar
P
Xiang
Xiaqin
X
Luo
Zhijan
Z
Ruderman
Neil
N
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D020672:I-kappa B Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; D007328:Insulin; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D011493:Protein Kinase C; D000263:Adenylate Kinase