FoxO transcription factors are required for hepatic HDL cholesterol clearance
Samuel X. Lee, … , Franz Rinninger, Rebecca A. Haeusler
Samuel X. Lee, … , Franz Rinninger, Rebecca A. Haeusler
Published February 6, 2018
Citation Information: J Clin Invest. 2018;128(4):1615-1626. https://doi.org/10.1172/JCI94230.
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FoxO transcription factors are required for hepatic HDL cholesterol clearance

Abstract

Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR-BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver.

Authors

Samuel X. Lee, Markus Heine, Christian Schlein, Rajasekhar Ramakrishnan, Jing Liu, Gabriella Belnavis, Ido Haimi, Alexander W. Fischer, Henry N. Ginsberg, Joerg Heeren, Franz Rinninger, Rebecca A. Haeusler

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Figure 5

Uptake of 125I-TC–/[3H]CEt-WT-HDL by hepatocytes isolated from chow-fed L-FoxO1,3,4 mice.

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Uptake of 125I-TC–/[3H]CEt-WT-HDL by hepatocytes isolated from chow-fed ...
(A and B) Hepatocytes from chow-fed L-FoxO1,3,4 mice and littermate controls were incubated (37°C, 2 hours) in medium containing 125I-TC–/[3H]CEt-WT-HDL (10, 20, 40, or 100 μg HDL protein/ml). Finally, cells were harvested, and apparent HDL particle uptake was analyzed as outlined in Methods. Values represent the mean of (A) n = 3 (control) and (B) n = 3 (L-FoxO1,3,4) independent determinations. An independent similar experiment yielded qualitatively identical results. Where no error bars are visible, the SEM was smaller than the symbol. (C) Western blots of SR-BI in primary hepatocytes from L-FoxO1,3,4 mice and littermate controls. Representative bands are shown. Two independent experiments yielded qualitatively identical results. (D) Relative Scarb1 and Lipc expression by qPCR in hepatocytes from chow-fed L-FoxO1,3,4 mice and littermate controls at different stages of the cell isolation procedure (see Methods). (A and B) §§§P < 0.001 and §§§§P < 0.0001, comparing [3H]CEt between L-FoxO1,3,4 and control hepatocytes; ***P < 0.001 and ****P < 0.0001, comparing [3H]CEt – 125I-TC between L-FoxO1,3,4 and control hepatocytes; and †P < 0.05 and ††P < 0.01, comparing 125I-TC between L-FoxO1,3,4 and control hepatocytes (Student’s t test). (D) ¶¶P < 0.01, ¶¶¶P < 0.001, and ¶¶¶¶P < 0.0001, comparing gene expression between L-FoxO1,3,4 and control hepatocytes at each stage; #P < 0.05, ##P < 0.01, ###P < 0.001, and ####P < 0.0001, comparing gene expression between control hepatocytes at baseline (before filtering) and control hepatocytes at each stage; and ‡‡P < 0.01 and ‡‡‡‡P < 0.0001, comparing gene expression between L-FoxO1,3,4 hepatocytes at baseline (before filtering) and L-FoxO1,3,4 hepatocytes at each stage (2-way ANOVA, followed by Tukey’s post hoc test). All data are presented as the mean ± SEM.