TitleDocosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways.
Publication TypeJournal Article
Year of Publication2006
AuthorsBotolin, D, Wang, Y, Christian, B, Jump, DB
JournalJ Lipid Res
Volume47
Issue1
Pagination181-92
Date Published2006 Jan
ISSN0022-2275
KeywordsAnimals, Base Sequence, Cell Nucleus, Dietary Fats, Docosahexaenoic Acids, Hepatocytes, Insulin, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Male, MAP Kinase Signaling System, Membrane Proteins, Protease Inhibitors, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Rats, Rats, Sprague-Dawley, RNA, Messenger, Sterol Regulatory Element Binding Protein 1
Abstract
 

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.

DOI10.1194/jlr.M500365-JLR200
Alternate JournalJ. Lipid Res.
PubMed ID16222032
PubMed Central IDPMC2764363
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
R01 DK043220-14 / DK / NIDDK NIH HHS / United States