[HTML][HTML] FoxO transcription factors are required for hepatic HDL cholesterol clearance

SX Lee, M Heine, C Schlein… - The Journal of …, 2018 - Am Soc Clin Investig
SX Lee, M Heine, C Schlein, R Ramakrishnan, J Liu, G Belnavis, I Haimi, AW Fischer
The Journal of clinical investigation, 2018Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation