FoxO transcription factors are required for hepatic HDL cholesterol clearance

• 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
• Format: Article
• Language: English
• 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci94230

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.