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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Research Article Metabolism

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 1

Plasma cholesterol profiles of chow-fed and WTD-fed L-FoxO1,3,4 mice.

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Plasma cholesterol profiles of chow-fed and WTD-fed L-FoxO1,3,4 mice. (A...
(A) Total plasma cholesterol in chow-fed L-FoxO1,3,4 mice and littermate controls after a 5-hour fast (n = 5). Data are presented as the mean ± SEM. (B) Cholesterol levels in plasma fractionated by FPLC in the same mice as in A. (C) Western blot of plasma apoA-I and apoE from pooled pairs of fractionated plasma obtained from FPLC in B. (D) Total plasma cholesterol levels in WTD-fed L-FoxO1,3,4 mice and littermate controls after a 5-hour fast (n = 5). (E) Cholesterol levels in plasma fractionated by FPLC in the same mice as in D. (F) Western blot of plasma apoA-I and apoE from pooled pairs of fractionated plasma obtained from FPLC in E. Independent FPLC cholesterol profiles for both chow-fed and WTD-fed mice yielded qualitatively identical results. Data are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.