出版社：American Society for Biochemistry and Molecular Biology
摘要：Insulin induces and dietary n-3 PUFAs suppress hepatic de novolipogenesis by controlling sterol-regulatory element bindingprotein-1 nuclear abundance (nSREBP-1). Our goal was to definethe mechanisms involved in this regulatory process. Insulintreatment of rat primary hepatocytes rapidly augments nSREBP-1and mRNASREBP-1c while suppressing mRNAInsig-2 but not mRNAInsig-1.These events are preceded by rapid but transient increases inAkt and Erk phosphorylation. Removal of insulin from hepatocytesleads to a rapid decline in nSREBP-1 [half-time (T1/2) 10 h]that is abrogated by inhibitors of 26S proteasomal degradation.22:6,n-3, the major n-3 PUFA accumulating in livers of fishoil-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 ofhepatocyte nSREBP-1 (T1/2 4 h) through a 26S proteasome-dependentprocess. 22:6,n-3 has minimal effects on microsomal SREBP-1and sterol-regulatory element binding protein cleavage-activatingprotein or nuclear SREBP-2. 22:6,n-3 transiently inhibits insulin-inducedAkt phosphorylation but induces Erk phosphorylation. Inhibitorsof Erk phosphorylation, but not overexpressed constitutivelyactive 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 mechanismfor n-3 PUFA regulation of hepatocyte nSREBP-1 and lipid metabolism.Supplementary key words sterol regulatory element binding protein-1 • Insig-1 • Insig-2
Abbreviations: ER, endoplasmic reticulum; LXR, liver X receptor; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3-kinase; SCAP, sterol-regulatory element binding protein cleavage-activating protein; SREBP, sterol-regulatory element binding protein; T1/2, half-time
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, 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 
