HDL metabolism in context: looking on the bright side

PURPOSE OF REVIEW: To review new data concerning HDL metabolism and cardiovascular disease, the concept of HDL 'functionality', and HDL kinetics in the metabolic syndrome. RECENT FINDINGS: HDL-apoA-I and apoA-II may be better predictors of cardiovascular disease than HDL-cholesterol. Cholesteryl ester transfer protein inhibition with torcetrapib does not benefit cardiovascular disease; whether this is related to 'congestion' of HDL transport or a specific off-target vasopressor effect remains unclear. Accelerated catabolism of HDL particles in metabolic syndrome could be due to increased hepatic secretion of apoB and apoC-III, hepatic steatosis, and low plasma adiponectin. The role of serum amyloid A and homocysteine is uncertain. In metabolic syndrome, therapies that could favourably alter HDL transport include weight loss, fish oils, higher dose statins, and fibrates; 'balancing feedback' may offset reduced catabolism of HDL, fenofibrate being the only agent hitherto shown to increase apoA-I production. SUMMARY: Elevating HDL-apoA-I and apoA-II may be a more important therapeutic objective than increased HDL-cholesterol. Recent studies underscore the potential value of studying HDL functionality, particularly in the metabolic syndrome. Reverse cholesterol transport can only be reliably probed at present by studying the kinetics of HDL particles or apolipoproteins; new methods are needed for investigating cellular and whole body cholesterol turnover. In metabolic syndrome, HDL-raising therapies have differential impact on HDL kinetics, the optimal endpoint being to increase transport and concentration with unchanged or accelerated catabolism.     

Characterization of Epstein–Barr virus reactivation in a modeled spaceflight system

Epstein–Barr virus (EBV) is the causative agent of mononucleosis and is also associated with several malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma, among others. EBV reactivates during spaceflight, with EBV shedding in saliva increasing to levels ten times those observed pre‐and post‐flight. Although stress has been shown to increase reactivation of EBV, other factors such as radiation and microgravity have been hypothesized to contribute to reactivation in space. We used a modeled spaceflight environment to evaluate the influence of radiation and microgravity on EBV reactivation. BJAB (EBV‐negative) and Raji (EBV‐positive) cell lines were assessed for viability/apoptosis, viral antigen and reactive oxygen species expression, and DNA damage and repair. EBV‐infected cells did not experience decreased viability and increased apoptosis due to modeled spaceflight, whereas an EBV‐negative cell line did, suggesting that EBV infection provided protection against apoptosis and cell death. Radiation was the major contributor to EBV ZEBRA upregulation. Combining modeled microgravity and radiation increased DNA damage and reactive oxygen species while modeled microgravity alone decreased DNA repair in Raji cells. Additionally, EBV‐infected cells had increased DNA damage compared to EBV‐negative cells. Since EBV‐infected cells do not undergo apoptosis as readily as uninfected cells, it is possible that virus‐infected cells in EBV seropositive individuals may have an increased risk to accumulate DNA damage during spaceflight. More studies are warranted to investigate this possibility. J. Cell. Biochem. 114: 616–624, 2013. © 2012 Wiley Periodicals, Inc.     

Small HDL particles containing two apoA-I molecules are precursors in vivo to medium and large HDL particles containing three and four apoA-I molecules in nonhuman primates.

We hypothesized that small HDL particles, containing two apoA-I molecules but no apoA-II (LpAI), may be converted in vivo into medium and large HDL particles, containing three or four apoA-I molecules, respectively, and that more conversion will occur in animals with higher HDL concentrations. To test this possibility, kinetic studies of small LpAI were performed in African green monkeys with either high plasma HDL cholesterol concentrations (120 +/- 36 mg/dl, mean +/- SD, n = 3) or low plasma HDL cholesterol concentrations (40 +/- 13 mg/dl, n = 3). Tracer small LpAI was purified, without ultracentrifugation, by immunoaffinity and gel filtration. After injection, the specific activity of apoA-I in small, medium, and large HDL, consisting of both LpAI and LpAI:AII particles, was followed. A multicompartmental model was developed with the simultaneous analysis of urine and plasma turnover data for the kinetics of apoA-I in small, medium, and large HDL. These analyses indicated that small HDL is converted to either medium or large HDL with little or no interconversion of medium HDL and large HDL. Much of the metabolic conversion of small HDL occurs in a sequestered pool, effectively outside the circulating plasma, in a unidirectional manner before reentering the circulating plasma as medium or large HDL. The mean fractional catabolic rate of apoA-I in small, medium, and large HDL was not different comparing the high and low HDL group. In contrast, the mean production rate of apoA-I was greater in the high HDL group compared with the low HDL group. These data support the hypothesis that the plasma concentration of HDL is primarily a function of the rate of appearance of apoA-I in medium and large HDL.     

ErbB2 and ErbB3 receptors mediate inhibition of calcium-dependent chloride secretion in colonic epithelial cells

We have previously demonstrated that epidermal growth factor (EGF) inhibits calcium-dependent chloride secretion via a mechanism involving stimulation of phosphatidylinositol 3-kinase (PI3-K). The muscarinic agonist of chloride secretion, carbachol (CCh), also stimulates an antisecretory pathway that involves transactivation of the EGF receptor (EGFR) but does not involve PI3-K. Here, we have examined if ErbB receptors, other than the EGFR, have a role in regulation of colonic secretion and if differential effects on ErbB receptor activation may explain the ability of the EGFR to propagate diverse signaling pathways in response to EGF versus CCh. Basolateral, but not apical, addition of the ErbB3/ErbB4 ligand alpha-heregulin (HRG; 1-100 ng/ml) inhibited secretory responses to CCh (100 microM) across voltage-clamped T(84) epithelial cells. Immunoprecipitation/Western blot studies revealed that HRG (100 ng/ml) stimulated tyrosine phosphorylation and dimerization of ErbB3 and ErbB2, but had no effect on phosphorylation of the EGFR. HRG also stimulated recruitment of the p85 subunit of PI3-K to ErbB3/ErbB2 receptor dimers, while the PI3-K inhibitor, wortmannin (50 nM), completely reversed the inhibitory effect of HRG on CCh-stimulated secretion. Further studies revealed that, while both EGF (100 ng/ml) and CCh (100 microM) stimulated phosphorylation of the EGFR, only EGF stimulated phosphorylation of ErbB2, and neither stimulated ErbB3 phosphorylation. EGF, but not CCh, stimulated the formation of EGFR/ErbB2 receptor dimers and the recruitment of p85 to ErbB2. We conclude that ErbB2 and ErbB3 are expressed in T(84) cells and are functionally coupled to inhibition of calcium-dependent chloride secretion. Differential dimerization with other ErbB family members may underlie the ability of the EGFR to propagate diverse inhibitory signals in response to activation by EGF or transactivation by CCh.     

Human apolipoprotein A-I kinetics within triglyceride-rich lipoproteins and high density lipoproteins.

Stable isotope methodology was used to determine the kinetic behavior of apolipoprotein (apo) A-I within the triglyceride-rich lipoprotein (TRL) fraction and to compare TRL apoA-I kinetics with that of apoA-I in high density lipoprotein (HDL) and TRL apoB-48. Eight subjects (5 males and 3 females) over the age of 40 were placed on a baseline average American diet and after 6 weeks received a primed-constant infusion of [5,5,5-(2)H(3)]-l-leucine for 15 h while consuming small hourly meals of identical composition. HDL and TRL apoA-I and TRL apoB-48 tracer/tracee enrichment curves were obtained by gas chromatography;-mass spectrometry. Data were fitted to a compartmental model to determine the fractional secretion rates of apoA-I and apoB-48 within each lipoprotein fraction. Mean plasma apoA-I levels in TRL and HDL fractions were 0. 204 +/- 0.057 and 134 +/- 15 mg/dl, respectively. The mean fractional catabolic rate (FCR) of TRL apoA-I was 0.250 +/- 0.069 and HDL apoA-I was 0.239 +/- 0.054 pools/day, with mean estimated residence times (RT) of 4.27 and 4.37 days, respectively. The mean TRL apoB-48 FCR was 5.2 +/- 2.0 pools/day and the estimated mean RT was 5.1 +/- 1.8 h. Our results indicate that apoA-I is catabolized at a slower rate than apoB-48 within TRL, and that apoA-I within TRL and HDL fractions are catabolized at similar rates.     

Genomic instability and aging-like phenotype in the absence of mammalian SIRT6

The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.     

Hydraulic redistribution: limitations for plants in saline soils

Hydraulic redistribution (HR), the movement of water from wet to dry patches in the soil via roots, occurs in different ecosystems and plant species. By extension of the principle that HR is driven by gradients in soil water potential, HR has been proposed to occur for plants in saline soils. Despite the inherent spatial patchiness and salinity gradients in these soils, the lack of direct evidence of HR in response to osmotic gradients prompted us to ask the question: are there physical or physiological constraints to HR for plants in saline environments? We propose that build‐up of ions in the root xylem sap and in the leaf apoplast, with the latter resulting in a large predawn disequilibrium of water potential in shoots compared with roots and soil, would both impede HR. We present a conceptual model that illustrates how processes in root systems in heterogeneous salinity with water potential gradients, even if equal to those in non‐saline soils, will experience a dampened magnitude of water potential gradients in the soil–plant continuum, minimizing or preventing HR. Finally, we provide an outlook for understanding the relevance of HR for plants in saline environments by addressing key research questions on plant salinity tolerance.     

Importance of Hydrologic and Landscape Heterogeneity for Restoring Bank Swallow (Riparia riparia) Colonies along the Sacramento River, California

Human activities have degraded riparian systems in numerous ways, including homogenization of the floodplain landscape and minimization of extreme flows. We analyzed the effects of changes in these and other factors for extinction–colonization dynamics of a threatened Bank Swallow population along the upper Sacramento River, California, U.S.A. We monitored Bank Swallow distributions along a 160‐km stretch of the river from 1986–1992 and 1996–2003 and tested whether site extinctions and colonizations corresponded with changes in maximum river discharge, surrounding land cover, estimated colony size, temperature, and precipitation. Colonization probabilities increased with maximum discharge. Extinction probabilities decreased with proximity to the nearest grassland, decreased with colony size, and increased with maximum discharge. To explore the implications for restoration, we incorporated the statistically estimated effects of distance to grassland and maximum discharge into simple metapopulation models. Under current conditions, the Bank Swallow metapopulation appears to be in continued decline, although stable or increasing numbers cannot be ruled out with the existing data. Maximum likelihood parameters from these regression models suggest that the Sacramento River metapopulation could be restored to 45 colonies through moderate amounts of grassland restoration, large increases in discharge, or direct restoration of nesting habitat by removing approximately 10% of existing bank protection (riprap) from suitable areas. Our results highlight the importance of grassland restoration, mixed benefits of restoring high spring discharge, and the importance of within‐colony dynamics as areas for future research.     

Randomised trial of personalised computer based information for cancer patients

ObjectiveTo compare the use and effect of a computer based information system for cancer patients that is personalised using each patient''s medical record with a system providing only general information and with information provided in booklets.DesignRandomised trial with three groups. Data collected at start of radiotherapy, one week later (when information provided), three weeks later, and three months later.Participants525 patients started radical radiotherapy; 438 completed follow up.InterventionsTwo groups were offered information via computer (personalised or general information, or both) with open access to computer thereafter; the third group was offered a selection of information booklets.OutcomesPatients'' views and preferences, use of computer and information, and psychological status; doctors'' perceptions; cost of interventions.ResultsMore patients offered the personalised information said that they had learnt something new, thought the information was relevant, used the computer again, and showed their computer printouts to others. There were no major differences in doctors'' perceptions of patients. More of the general computer group were anxious at three months. With an electronic patient record system, in the long run the personalised information system would cost no more than the general system. Full access to booklets cost twice as much as the general system.ConclusionsPatients preferred computer systems that provided information from their medical records to systems that just provided general information. This has implications for the design and implementation of electronic patient record systems and reliance on general sources of patient information.