title: Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins.
abstract: The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50-90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston MA.
authors: Ji
authors: J
authors: Miao
authors: Joel T
authors: JT
authors: Haas
authors: Praveen
authors: P
authors: Manthena
authors: Yanning
authors: Y
authors: Wang
authors: Enpeng
authors: E
authors: Zhao
authors: Bhavapriya
authors: B
authors: Vaitheesvaran
authors: Irwin J
authors: IJ
authors: Kurland
authors: Sudha B
authors: SB
authors: Biddinger
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D053898:Biosynthetic Pathways / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis; D000069438:Ezetimibe; D005215:Fasting; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome
chemical_list: D001384:Azetidines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D008148:Lovastatin; D011972:Receptor, Insulin; D000069438:Ezetimibe
keywords: cholesterol biosynthesis; hepatic insulin signaling; liver insulin receptor knockout; sterol regulatory element binding protein