biostudies-literatureLee SXNIDDK NIH HHSNHLBI NIH HHSNIH1615-1626https://www.ebi.ac.uk/biostudies/studies/S-EPMC5873864biostudies-literatureUnknown128(4)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 couThe Journal of clinical investigationFoxO transcription factors are required for hepatic HDL cholesterol clearance.PMC5873864F31 HL132484R01 HL125649P30 DK026687R35 HL135833HL125649T32 DK007328T32 DK007647Schlein CLiu JHaimi IHeeren JHeine MFischer AWRinninger FLee SXBelnavis GGinsberg HNRamakrishnan RHaeusler RAfalseFoxO 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, 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 cou2018-01-01T00:00:00Z2018 Apr2025-04-26T03:38:51.271Z2019-03-26T23:44:12ZS-EPMC58738642940880910.1172/JCI9423010.1172/jci94230