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 7

Acute knockdown via Cre adeno-associated virus in chow-fed hepatic FoxO–floxed mice.

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Acute knockdown via Cre adeno-associated virus in chow-fed hepatic FoxO–...
(A–D) Chow-fed, adult Foxo1fl/fl, Foxo3fl/fl, and Foxo4fl/Y control mice transduced with adeno-associated virus (serotype 8) expressing Cre recombinase driven by the hepatocyte-specific Tbg promoter (AAV8.Tbg.Cre) or control virus (AAV.GFP) (n = 5). For comparison, we also included a group of traditional L-FoxO1,3,4–knockout mice that were not transduced with virus, but rather had FoxO deficiency since birth (n = 4). Four weeks after virus transduction, mice were fasted for five hours, and then plasma and livers were collected. (A) Cholesterol levels in plasma fractionated by FPLC 4 weeks after virus transduction. (B) Relative hepatic gene expression by qPCR. (C) Representative Western blot of hepatic SR-BI expression. SR-BI/actin denotes relative SR-BI expression levels by densitometric scanning. *P < 0.05 and **P < 0.01 versus AAV.GFP mice. No significant difference was detected between AAV8.Tbg.Cre mice and L-FoxO1,3,4 mice. (D) Correlation between Scarb1 or Lipc mRNA and FoxO1 mRNA. The P values in B and C were calculated by 1-way ANOVA, followed by a post hoc t test using the pooled SD, without Bonferroni’s correction. Data are presented as the mean ± SEM.