Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways.
Insulin induces and dietary n-3 PUFAs suppress hepatic de novo lipogenesis by controlling sterol-regulatory element binding protein-1 nuclear abundance (nSREBP-1). Our goal was to define the mechanisms involved in this regulatory process. Insulin treatment of rat primary hepatocytes rapidly augments nSREBP-1 and mRNA(SREBP-1c) while suppressing mRNA(Insig-2) but not mRNA(Insig-1). These events are preceded by rapid but transient increases in Akt and Erk phosphorylation. Removal of insulin from hepatocytes leads to a rapid decline in nSREBP-1 [half-time (T1/2) approximately 10 h] that is abrogated by inhibitors of 26S proteasomal degradation. 22:6,n-3, the major n-3 PUFA accumulating in livers of fish oil-fed rats, suppresses hepatocyte levels of nSREBP-1, mRNA(SREBP-1c), and mRNA(Insig-2) but modestly and transiently induces mRNA(Insig-1). More importantly, 22:6,n-3 accelerates the disappearance of hepatocyte nSREBP-1 (T1/2 approximately 4 h) through a 26S proteasome-dependent process. 22:6,n-3 has minimal effects on microsomal SREBP-1 and sterol-regulatory element binding protein cleavage-activating protein or nuclear SREBP-2. 22:6,n-3 transiently inhibits insulin-induced Akt phosphorylation but induces Erk phosphorylation. Inhibitors of Erk phosphorylation, but not overexpressed constitutively active Akt, rapidly attenuate 22:6,n-3 suppression of nSREBP-1. Thus, 22:6,n-3 suppresses hepatocyte nSREBP-1 through 26S proteasome- and Erk-dependent pathways. These studies reveal a novel mechanism for n-3 PUFA regulation of hepatocyte nSREBP-1 and lipid metabolism.
Botolin
Daniela
D
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Wang
Yun
Y
Christian
Barbara
B
Jump
Donald B
DB
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; C491574:Insig1 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C102196:SREBP cleavage-activating protein; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D004281:Docosahexaenoic Acids; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease