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Papers In Press, published online ahead of print October 12, 2005
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Physiology Dept., Michigan State University, East Lansing, MI 48824
Corresponding Author: jump{at}msu.edu
Insulin induces and dietary n-3 polyunsaturated fatty acids (PUFA) suppress hepatic de novo lipogenesis by controlling sterol regulatory element binding protein-1 nuclear abundance (nSREBP-1). Our goal was to define mechanisms involved in this regulatory process. Insulin treatment of rat primary hepatocytes rapidly augments nSREBP-1 and mRNASREBP-1c, while suppressing mRNAInsig-2, but not mRNAInsig-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 (T1/2 ~ 10 hrs) 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, mRNASREBP-1c and mRNAInsig-2, but modestly and transiently induces mRNAInsig-1. More importantly, 22:6,n-3 accelerates the disappearance of hepatocyte nSREBP-1 (T1/2~ 4 hrs) through a 26S proteasome-dependent process. 22:6,n-3 has minimal effects on microsomal SREBP-1 and SCAP, 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 SREBP-1 nuclear content through 26S proteasome- and Erk-dependent pathways. These studies reveal a novel mechanism for n-3 PUFA regulation of hepatocyte SREBP-1 nuclear abundance and lipid metabolism.
Revised on September 22, 2005
Accepted on October 11, 2005
Docosahexaneoic acid [22:6,n-3] regulates rat hepatocyte sterol regulatory element binding protein-1 (SREBP-1) nuclear abundance by Erk- and 26S proteasome-dependent pathways
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