Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones

Abstract

Impairment in HDL function associated with obesity and elevated serum triglyceride (TG) may be a major contributor to risk of coronary heart disease (CHD) in obese patients, yet mechanisms by which changes in metabolism impair HDL function are not well defi ned ( 1-6 ). Increased TGs in the form of VLDL give rise to low levels of HDL in part due to the actions of cholesteryl ester transfer protein (CETP), which shuttles TG and cholesteryl esters between serum lipoproteins. Because of lipid exchange, elevated serum VLDL leads to TG enrichment of HDL. This TG enrichment reduces the affinity of apolipoprotein A1 (apoA1) for cholesterol, promotes clearance of apoA1, and decreases HDL particle number ( 1, 3, 7 ). In addition, changes in the function of HDL related to infl ammation, coagulation, and reverse cholesterol transport are associated with obesity and metabolic diseases. HDL proteomics have revealed changes in apolipoproteins, infl ammatory proteins, and coagulation proteins in individuals with known Abstract Mechanisms underlying changes in HDL composition caused by obesity are poorly defi ned, 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 HFDfeeding 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 HFDinduced 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 infl uences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to defi ne how metabolic changes affect HDL composition and function.

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation

“…Mass spectrometry FLAG peptide eluates from three immunoprecipitation experiments from FLAG-SETD5-transfected and mock transfected cells were combined and analyzed by multidimensional protein identification technology (MudPIT) as previously described (Martinez et al, 2012).…”

Impact of Gastrectomy on High-Density Lipoprotein Cholesterol Elevation in Nonobese Patients During a 10-Year Follow-up

“…In women, menopause is associated with dyslipidemia, characterized by an increased very-low-density lipoprotein triglyceride level and a decreased HDL-C level 27) . In the present study, the HDL-C level increased after gastrectomy regardless of sex.…”

Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma

“…Shotgun proteomic analysis was performed by first suspending the samples in LDS sample buffer (Life Technologies), resolving the proteins approximately 1 cm using a 10% Novex pre-cast gel, and then performing in-gel tryptic digestion to recover peptides. These peptides were analyzed via MudPIT (Multidimensional Protein Identification Technology) essentially as previously described [5,6]. Briefly, digested peptides were loaded onto a biphasic pre-column consisting of 4 cm of reversed phase (RP) material followed by 4 cm of strong cation exchange RP material.…”