Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones.
Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function.
Department of Molecular Physiology & Biophysics.
Melissa N
MN
Martinez
Tennessee Valley Healthcare System; Division of Diabetes, Endocrinology, & Metabolism.
Christopher H
CH
Emfinger
Department of Molecular Physiology & Biophysics; University of North Carolina, Chapel Hill.
Matthew
M
Overton
Department of Biomedical Informatics.
Salisha
S
Hill
Department of Molecular Physiology & Biophysics.
Tara S
TS
Ramaswamy
Department of Molecular Physiology & Biophysics.
David A
DA
Cappel
Division of Diabetes, Endocrinology, & Metabolism; Wuhan University.
Ke
K
Wu
Atherosclerosis Research Unit, Division of Cardiovascular Medicine.
Sergio
S
Fazio
Mass Spectroscopy Research Center Vanderbilt University School of Medicine.
W Hayes
WH
McDonald
Mass Spectroscopy Research Center Vanderbilt University School of Medicine.
David L
DL
Hachey
Department of Biomedical Informatics.
David L
DL
Tabb
Department of Molecular Physiology & Biophysics; Tennessee Valley Healthcare System; Division of Diabetes, Endocrinology, & Metabolism. Electronic address: john.stafford@vanderbilt.edu.
John M
JM
Stafford
D000818:Animals; D053304:Apolipoprotein C-II / Q000097:blood; D001054:Apolipoproteins A / Q000097:blood; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced; D007328:Insulin / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D053304:Apolipoprotein C-II; D001054:Apolipoproteins A; D053480:Cholesterol Ester Transfer Proteins; D007328:Insulin; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C022205:apolipoprotein A-IV; D002784:Cholesterol