Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice
Seongah Han, … , Domenico Accili, Alan R. Tall
Seongah Han, … , Domenico Accili, Alan R. Tall
Published March 9, 2009
Citation Information: J Clin Invest. 2009;119(4):1029-1041. https://doi.org/10.1172/JCI36523.
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Research Article Cardiology

Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice

Abstract

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.

Authors

Seongah Han, Chien-Ping Liang, Marit Westerterp, Takafumi Senokuchi, Carrie L. Welch, Qizhi Wang, Michihiro Matsumoto, Domenico Accili, Alan R. Tall

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Figure 2

Plasma lipoprotein profiles, plasma lipoprotein cholesterol, Tg and apoB levels, and Tg and apoB production of Ldlr–/– and L1B6Ldlr–/– mice.

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Plasma lipoprotein profiles, plasma lipoprotein cholesterol, Tg and apoB...
(A) Lipoprotein separation by FPLC. Pooled plasma from 10 Ldlr–/– (circles) and 10 L1B6Ldlr–/– (squares) mice described in Figure 1A were used for FPLC analysis. Plasma was collected after 5 hours of fasting. Fractions were used to quantify plasma lipoprotein cholesterol concentration. (B) Quantification of plasma VLDL cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), VLDL-Tg, and LDL-Tg from Ldlr–/– (white bars) and L1B6Ldlr–/– (black bars) mice. Plasma was collected from mice fed WTD for 2 weeks, after a 5-hour fast (n = 13–14; *P < 0.001). (C) Representative sample of apoB (apoB100 [B100] and apoB48 [B48]) levels in Ldlr–/– and L1B6Ldlr–/– mice shown in B. apoB-containing lipoproteins (VLDL and LDL) isolated by ultracentrifugation were resolved by SDS-PAGE and visualized by Coomassie blue staining. Each lane represents an individual mouse. apoB was normalized to the amount in the Ldlr–/– controls (n = 5; **P < 0.01). (D) Tg and apoB production in Ldlr–/– and L1B6Ldlr–/– mice. Tg production was determined by measuring plasma Tg concentrations at indicated times after Triton WR-1339 injection (n = 4–5). Equal amounts of plasma from each mouse 2 hours after injection with 35S-methionine was resolved by SDS-PAGE to visualize 35S-methionine–labeled apoB proteins. Similar results were obtained from 2 independent experiments.