Details

Autor(en) / Beteiligte

• Botolin, Daniela
• Wang, Yun
• Christian, Barbara
• Jump, Donald B

Titel

Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways

Ist Teil von

• Journal of lipid research, 2006-01, Vol.47 (1), p.181-192

Ort / Verlag

United States: Elsevier

Erscheinungsjahr

2006

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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[subscript SREBP-1c] while suppressing mRNA[subscript Insig-2] but not mRNA[subscript 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 (T[subscript 1/2]) [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[subscript SREBP-1c], and mRNA[subscript Insig-2] but modestly and transiently induces mRNA[subscript Insig-1]. More importantly, 22:6,n-3 accelerates the disappearance of hepatocyte nSREBP-1 (T[subscript 1/2] [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.