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FoxO transcription factors are required for hepatic HDL cholesterol clearance

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,...

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Published in:The Journal of clinical investigation 2018-04, Vol.128 (4), p.1615-1626
Main Authors: Lee, Samuel X, Heine, Markus, Schlein, Christian, Ramakrishnan, Rajasekhar, Liu, Jing, Belnavis, Gabriella, Haimi, Ido, Fischer, Alexander W, Ginsberg, Henry N, Heeren, Joerg, Rinninger, Franz, Haeusler, Rebecca A
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container_title The Journal of clinical investigation
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creator Lee, Samuel X
Heine, Markus
Schlein, Christian
Ramakrishnan, Rajasekhar
Liu, Jing
Belnavis, Gabriella
Haimi, Ido
Fischer, Alexander W
Ginsberg, Henry N
Heeren, Joerg
Rinninger, Franz
Haeusler, Rebecca A
description 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.
doi_str_mv 10.1172/jci94230
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source PubMed Central; EZB Electronic Journals Library
subjects Apolipoproteins
Biomedical research
Cholesterol
Chromatography
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Enzymes
Forkhead protein
FOXO1 protein
Gene silencing
Genetic aspects
Health aspects
High density lipoprotein
Homeostasis
Insulin
Insulin resistance
Lipase
Lipid metabolism
Lipids
Liver
Low density lipoprotein
Metabolism
Phenotypes
Proteins
Rodents
Scavenger receptors
Transcription factors
title FoxO transcription factors are required for hepatic HDL cholesterol clearance
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