A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.

Oxidized phospholipids (OxPLs) on apolipoprotein B-100 (apoB-100) particles are strongly associated with lipoprotein [a] (Lp[a]). In this study, we evaluated whether Lp[a] is preferentially the carrier of OxPL in human plasma. The content of OxPL on apoB-100 particles was measured with monoclonal antibody E06, which recognizes the phosphocholine (PC) headgroup of oxidized but not native phospholipids. To assess whether OxPLs were preferentially bound by Lp[a] as opposed to other lipoproteins, immunoprecipitation and ultracentrifugation experiments, in vitro transfer studies, and chemiluminescent ELISAs were performed. Immunoprecipitation of Lp[a] from human plasma with an apolipoprotein [a] (apo[a])-specific antibody demonstrated that more than 85% of E06 reactivity (i.e., OxPL) coimmunoprecipitated with Lp[a]. Ultracentrifugation experiments showed that nearly all OxPLs were found in fractions containing apo[a], as opposed to other apolipoproteins. In vitro transfer studies showed that oxidized LDL preferentially donates OxPLs to Lp[a], as opposed to LDL, in a time- and temperature-dependent manner, even in aqueous buffer. Approximately 50% of E06 immunoreactivity could be extracted from isolated Lp[a] following exposure of plasma to various lipid solvents. These data demonstrate that Lp[a] is the preferential carrier of PC-containing OxPL in human plasma. This unique property of Lp[a] suggests novel insights into its physiological function and mechanisms of atherogenicity.

Dyslipidemia in children with type 2 diabetes vs. obesity.

OBJECTIVE: To compare the frequency and severity of dyslipidemia between subjects with type 2 diabetes (T2DM) and non-diabetic obese group (OB) subjects, followed in a pediatric subspecialty clinic. RESEARCH DESIGN AND METHODS: One hundred and four OB subjects seen consecutively by one physician and 67 pediatric subjects diagnosed with T2DM (negative antibodies) were screened from an institutional review board-approved database. Fifty-two T2DM and 75 OB subjects with fasting lipid profiles measured at one hospital's laboratory were included. RESULTS: Both OB and T2DM subjects were predominantly Mexican American. Comparing T2DM at diagnosis or uncontrolled (UC) and OB, mean +/- SD age was 14.3 +/- 2.3 and 11.4 +/- 3.7 with body mass index-Z score of 2.02 +/- 0.67 and 2.46 +/- 0.45, respectively (both p < 0.01). Comparing lipid levels in T2DM to OB and National Health and Nutrition Examination Survey III, the percentage of subjects, respectively, with cholesterol >200 mg/dL (5.17 mmol/L) were 55.8, 22.7, and 10%; with low-density lipoprotein >130 mg/dL (3.36 mmol/L) were 39.4, 12.5, and 10%; with triglycerides >150 mg/dL (1.68 mmol/L) were 65.1, 38.7, and 12.5%; and with high-density lipoprotein <35 mg/dL (0.91 mmol/L) were 40, 22.2, and 10%. Over 80% of the T2DM subjects improved their lipid profile with improved glycemic control as hemoglobin A1c decreased from 10.85 +/- 2.17 to 7.6 +/- 2%. CONCLUSIONS: Dyslipidemia is a frequent comorbidity of obesity and T2DM, starting in childhood, and poses a major public health risk. Dyslipidemia in pediatric subjects with UC T2DM is significantly worse than in OB subjects but is similar to OB subjects when diabetes was better controlled. Earlier use of lipid-lowering drugs should be considered in pediatric T2DM patients who achieve tight glycemic control, yet their dyslipidemia persists.

Increased luteinizing hormone pulse frequency in obese oligomenorrheic girls with no evidence of hyperandrogenism.

OBJECTIVE: To determine whether obese, nonhirsute adolescents with oligomenorrhea exhibit similar increased LH pulse secretion patterns compared with obese girls with polycystic ovary syndrome (PCOS). DESIGN: Prospective, observational study. SETTING: Tertiary university hospital. PATIENT(S): Nine obese girls with oligomenorrhea, 15 with PCOS, and 10 controls. INTERVENTION(S): Twenty-four-hour IV blood sampling for LH (every 10 minutes); measurement of steroid hormones (every 12 hours); and injection of leuprolide acetate (10 microgm/kg SC). MAIN OUTCOME MEASURE(S): Twenty-four-hour, wake, and sleep LH mean serum concentration, pulse frequency, amplitude; steroid hormones, including free androgen index (FAI); and pre- and post-leuprolide acetate 17-hydroxyprogesterone measurements. RESULT(S): Twenty-four-hour LH pulse frequency in oligomenorrheic girls (18.6 +/- 1.2) (mean +/- SE) was comparable to that in girls with PCOS (20.9 +/- 0.7) and greater than in normal girls (13.4 +/- 0.8). The pulse number during both sleep and wake was identical in oligomenorrheic and PCOS girls and significantly greater than that of normal girls. Mean 24-hour LH level, serum androgen levels, and FAI in oligomenorrheic girls were equivalent to those of normal controls and lower than those of PCOS girls. CONCLUSION(S): These preliminary results indicate that obese girls with oligomenorrhea exhibit increased LH pulse frequency in the absence of clinical and/or biochemical evidence of hyperandrogenism.

Endocrine abnormalities in patients with Jacobsen (11q-) syndrome.

Jacobsen syndrome (JS), a rare disorder with multiple dysmorphic features, is caused by the terminal deletion of chromosome 11q. Short stature has been reported in this syndrome, however very few of these patients have undergone endocrine evaluation. Serum insulin-like growth factor-1 (IGF-1) levels are an indirect indicator of growth hormone activity and are a useful initial screening tool in the assessment of an individual's growth hormone axis. We studied nine children with JS, eight of whom had short stature. Four out of eight children with short stature (50%) had low IGF-1 values, with three low for age and one low for Tanner stage. Four out of six males (67%) had cryptorchidism, a potential sign of hypogonadism. We conclude that low IGF-1 is common in patients with JS and short stature, and that growth hormone status and possibly hypothalamic-pituitary function should be evaluated in this patient population.

Type 2 diabetes mellitus in adolescence: lipid and cardiovascular risk factors.

This review discusses the important consequences of dyslipidemia and arteriosclerosis in type 2 diabetes as documented in studies in adults. It then examines the relatively recent upsurge in type 2 diabetes in children and adolescents, its characteristics, and its importance in directing our attention to cardiovascular risk factors in this age group. The discussion concludes with an examination of the information available about arteriosclerosis in the young and about the treatment of hypercholesterolemia in children and adolescents.

Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.