The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity.
Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-lambda knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFkappaB (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkappaB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkappaB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.
Sajan
Mini P
MP
James A. Haley Veterans Hospital, Tampa, FL, USA.
Standaert
Mary L
ML
Nimal
Sonali
S
Varanasi
Usha
U
Pastoor
Tina
T
Mastorides
Stephen
S
Braun
Ursula
U
Leitges
Michael
M
Farese
Robert V
RV
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
D017931:DNA Primers; D004041:Dietary Fats; D051550:I-kappa B Kinase; D007328:Insulin; D007527:Isoenzymes; D016328:NF-kappa B; D011493:Protein Kinase C; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D000099293:Protein Kinase C-lambda; C497388:Srebf1 protein, mouse; C496562:Ikbkb protein, mouse; C115015:PKC-3 protein