Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance and type 2 diabetes mellitus, but the molecular signals linking hepatic fat accumulation to hepatic insulin resistance are unknown. Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance. In this setting, PKCepsilon, but not other isoforms of PKC, is activated. To determine whether PKCepsilon plays a causal role in the pathogenesis of hepatic insulin resistance, we treated rats with an antisense oligonucleotide against PKCepsilon and subjected them to 3 days of high-fat feeding. Knocking down PKCepsilon expression protects rats from fat-induced hepatic insulin resistance and reverses fat-induced defects in hepatic insulin signaling. Furthermore, we show that PKCepsilon associates with the insulin receptor in vivo and impairs insulin receptor kinase activity both in vivo and in vitro. These data support the hypothesis that PKCepsilon plays a critical role in mediating fat-induced hepatic insulin resistance and represents a novel therapeutic target for type 2 diabetes.
Samuel
Varman T
VT
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Liu
Zhen-Xiang
ZX
Wang
Amy
A
Beddow
Sara A
SA
Geisler
John G
JG
Kahn
Mario
M
Zhang
Xian-man
XM
Monia
Brett P
BP
Bhanot
Sanjay
S
Shulman
Gerald I
GI
D000818:Animals; D005234:Fatty Liver / Q000201:enzymology*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000819:agonists; D015398:Signal Transduction
D007328:Insulin; D016376:Oligonucleotides, Antisense; D011972:Receptor, Insulin; D051744:Protein Kinase C-epsilon