title: Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice.
abstract: Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism.
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN Department of Molecular Physiology and Biophysics Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Palmisano
authors.affiliation: Department of Molecular Physiology and Biophysics Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Thao D
authors.initials: TD
authors.lastname: Le
authors.affiliation: Department of Molecular Physiology and Biophysics Vanderbilt University Medical Center, Nashville, TN Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Yoon Kwang
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN Department of Molecular Physiology and Biophysics Vanderbilt University Medical Center, Nashville, TN Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN john.stafford@vanderbilt.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Stafford
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000502:physiology; D005260:Female; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood*
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D014280:Triglycerides
keywords: estrogen; estrogen receptor alpha; lipid and lipoprotein metabolism; small heterodimer partner; triglycerides; very low density lipoprotein