Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.
Type 2 diabetes is associated with accelerated atherogenesis, which may result from a combination of factors, including dyslipidemia characterized by increased VLDL secretion, and insulin resistance. To assess the hypothesis that both hepatic and peripheral insulin resistance contribute to atherogenesis, we crossed mice deficient for the LDL receptor (Ldlr-/- mice) with mice that express low levels of IR in the liver and lack IR in peripheral tissues (the L1B6 mouse strain). Unexpectedly, compared with Ldlr-/- controls, L1B6Ldlr-/- mice fed a Western diet showed reduced VLDL and LDL levels, reduced atherosclerosis, decreased hepatic AKT signaling, decreased expression of genes associated with lipogenesis, and diminished VLDL apoB and lipid secretion. Adenovirus-mediated hepatic expression of either constitutively active AKT or dominant negative glycogen synthase kinase (GSK) markedly increased VLDL and LDL levels such that they were similar in both Ldlr-/- and L1B6Ldlr-/- mice. Knocking down expression of hepatic IR by adenovirus-mediated shRNA decreased VLDL triglyceride and apoB secretion in Ldlr-/- mice. Furthermore, knocking down hepatic IR expression in either WT or ob/ob mice reduced VLDL secretion but also resulted in decreased hepatic Ldlr protein. These findings suggest a dual action of hepatic IR on lipoprotein levels, in which the ability to increase VLDL apoB and lipid secretion via AKT/GSK is offset by upregulation of Ldlr.
Han
Seongah
S
Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168th St., New York, New York 10032, USA. sh2068@columbia.edu
Liang
Chien-Ping
CP
Westerterp
Marit
M
Senokuchi
Takafumi
T
Welch
Carrie L
CL
Wang
Qizhi
Q
Matsumoto
Michihiro
M
Accili
Domenico
D
Tall
Alan R
AR
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D050155:Lipogenesis; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
D001055:Apolipoproteins B; D007328:Insulin; D008055:Lipids; D008079:Lipoproteins, VLDL; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3