Vascular Disease Is Associated With the Expression of Genes for Intestinal Cholesterol Transport and Metabolism.

Context: Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. Objective: This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. Design/Patients: One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. Results: There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. Conclusion: Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.

Postprandial Studies Uncover Differing Effects on HDL Particles of Overt and Subclinical Hypothyroidism.

BACKGROUND: Overt hypothyroidism (OH) is associated with abnormal lipid metabolism and endothelial dysfunction under fasting conditions. The balance of evidence suggests similar but less marked abnormalities in subclinical hypothyroidism (SCH). There are few data regarding the metabolic and vascular effects of OH or SCH under postprandial conditions. METHODS: This was a cross-sectional study, carried out in a teaching hospital. Subjects with OH (n = 21), SCH (n = 28), and controls (n = 44) matched for age, sex, and body mass index (BMI) were studied under fasting and postprandial conditions. Postprandial lipid metabolism with particular emphasis on intestinally derived lipoproteins, HDL cholesterol (HDL), and endothelial function were compared in subjects with OH and SCH who were matched for age, sex, and BMI. Apolipoprotein B48 (Apo B48), a measure of intestinally derived lipoprotein, was measured by enzyme-linked immunosorbent assay. HDL was subfractionated into HDL2 and HDL3 by rapid ultracentrifugation. Functional aspects of HDL were determined by monitoring the activities of cholesteryl-ester-transfer-protein (CETP) and lecithin-cholesterol-acyl-transferase (LCAT). Systemic and HDL-associated inflammation was assessed by measuring serum-amyloid-A (SAA) levels. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery in response to hyperemia of the forearm. RESULTS: There were no significant between-group differences in LDL cholesterol or triglyceride concentration. Peak Apo B48 levels were greater in OH (p < 0.001) and SCH (p < 0.05) compared with control subjects. HDL area under the curve (AUC) was lower postprandially in SCH (p < 0.001) but not OH compared with control subjects. HDL2- and HDL3-associated CETP AUC was lower only in OH (p < 0.005) compared with controls. FMD was reduced in OH (p < 0.05) compared with SCH and controls postprandially. CONCLUSION: Postprandial lipoprotein and vascular abnormalities differ between OH and SCH. Although both are characterized by increased intestinally derived lipoprotein particles, HDL is reduced only in SCH. Maintained HDL in OH probably reflects reduced CETP activity, which was not observed in SCH. Postprandial endothelial dysfunction is abnormal only in OH, and this effect does not appear to reflect increased inflammation.