ApoF knockdown increases cholesteryl ester transfer to LDL and impairs cholesterol clearance in fat-fed hamsters

Cholesteryl ester transfer protein (CETP) regulates intravascular lipoprotein metabolism. In vitro studies indicate that ApoF alters CETP function by inhibiting its activity with LDL. To explore in vivo the complexities driving ApoF's effects on CETP, we developed a siRNA-based hamster model of ApoF knockdown. In both male and female hamsters on chow- or fat-fed diets, we measured lipoprotein levels and composition, determined CETP-mediated transfer of cholesteryl esters (CEs) between lipoproteins, and quantified reverse cholesterol transport (RCT). We found that apoF knockdown in chow-fed hamsters had no effect on lipoprotein levels or composition, but these ApoF-deficient lipoproteins supported 50–100% higher LDL CETP activity in vitro. ApoF knockdown in fat-fed male hamsters created a phenotype in which endogenous CETP-mediated CE transfer from HDL to LDL increased up to 2-fold, LDL cholesterol increased 40%, HDL declined 25%, LDL and HDL lipid compositions were altered, and hepatic LDLR gene expression was decreased. Diet-induced hypercholesterolemia obscured this phenotype on occasion. In fat-fed female hamsters, ApoF knockdown caused similar but smaller changes in plasma CETP activity and LDL cholesterol. Notably, ApoF knockdown impaired HDL RCT in fat-fed hamsters but increased sterol excretion in chow-fed animals. These in vivo data validate in vitro findings that ApoF regulates lipid transfer to LDL. The consequences of ApoF knockdown on lipoproteins and sterol excretion depend on the underlying lipid status. By minimizing the transfer of HDL-derived CE to LDL, ApoF helps control LDL cholesterol levels when LDL clearance mechanisms are limiting. Cholesteryl ester transfer protein (CETP) regulates intravascular lipoprotein metabolism. In vitro studies indicate that ApoF alters CETP function by inhibiting its activity with LDL. To explore in vivo the complexities driving ApoF's effects on CETP, we developed a siRNA-based hamster model of ApoF knockdown. In both male and female hamsters on chow- or fat-fed diets, we measured lipoprotein levels and composition, determined CETP-mediated transfer of cholesteryl esters (CEs) between lipoproteins, and quantified reverse cholesterol transport (RCT). We found that apoF knockdown in chow-fed hamsters had no effect on lipoprotein levels or composition, but these ApoF-deficient lipoproteins supported 50–100% higher LDL CETP activity in vitro. ApoF knockdown in fat-fed male hamsters created a phenotype in which endogenous CETP-mediated CE transfer from HDL to LDL increased up to 2-fold, LDL cholesterol increased 40%, HDL declined 25%, LDL and HDL lipid compositions were altered, and hepatic LDLR gene expression was decreased. Diet-induced hypercholesterolemia obscured this phenotype on occasion. In fat-fed female hamsters, ApoF knockdown caused similar but smaller changes in plasma CETP activity and LDL cholesterol. Notably, ApoF knockdown impaired HDL RCT in fat-fed hamsters but increased sterol excretion in chow-fed animals. These in vivo data validate in vitro findings that ApoF regulates lipid transfer to LDL. The consequences of ApoF knockdown on lipoproteins and sterol excretion depend on the underlying lipid status. By minimizing the transfer of HDL-derived CE to LDL, ApoF helps control LDL cholesterol levels when LDL clearance mechanisms are limiting. ApoF is a minor apolipoprotein found predominately on HDL but also bound to LDL (1He Y. Greene D.J. Kinter M. Morton R.E. Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex.J. Lipid Res. 2008; 49: 1529-1537Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 2Morton R.E. Greene D.J. Conversion of lipid transfer inhibitor protein (apolipoprotein F) to its active form depends on LDL composition.J. Lipid Res. 2011; Full Text Full Text PDF PubMed Scopus Google The gene a protein a and a is by a between activity and lipid PubMed Scopus Google to which is of from the of Morton R.E. and expression of lipid transfer inhibitor protein its with apolipoprotein Full Text Full Text PDF PubMed Scopus Google Cholesteryl ester transfer protein (CETP) the of cholesteryl ester and between its to CE in lipoprotein in R.E. of by the protein from Full Text PDF PubMed Google CETP lipoprotein and lipoprotein R.E. 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We a plasma protein that regulates CETP activity R.E. plasma inhibitor of and cholesteryl ester transfer Full Text PDF PubMed Google and determined that this lipid transfer inhibitor is to ApoF Morton R.E. and expression of lipid transfer inhibitor protein its with apolipoprotein Full Text Full Text PDF PubMed Scopus Google we ApoF to a CETP in vitro studies the a function (1He Y. Greene D.J. Kinter M. Morton R.E. Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex.J. Lipid Res. 2008; 49: 1529-1537Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 2Morton R.E. Greene D.J. Conversion of lipid transfer inhibitor protein (apolipoprotein F) to its active form depends on LDL composition.J. Lipid Res. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, R.E. Greene D.J. of lipid transfer between lipoproteins by an endogenous plasma lipoprotein Lipid Res. 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