Patricia Huebbe

Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review

Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimers disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex.ApoE4 seems to be protective against chronic hepatitis C virus infection and retards fibrosis progression. In contrast apoE4 enhances the fusion rate of human immunodeficiency virus with target cell membranes, resulting in accelerated cell entry and faster disease progression. Its association with human immunodeficiency virus-associated dementia remains controversial. Regarding herpes simplex virus infection, apoE4 intensifies virus latency and is associated with increased oxidative damage of the central nervous system, and there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with an increased risk of Alzheimers disease. In addition to reviewing available data from human trials, evidence derived from a variety of cell culture and animal models are considered in this review in order to provide mechanistic insights into observed association between apoE4 genotype and viral disease infection and pathology.

Nutrition and Healthy Ageing: Calorie Restriction or Polyphenol-Rich ''MediterrAsian'' Diet?

Diet plays an important role in mammalian health and the prevention of chronic diseases such as cardiovascular disease (CVD). Incidence of CVD is low in many parts of Asia (e.g., Japan) and the Mediterranean area (e.g., Italy, Spain, Greece, and Turkey). The Asian and the Mediterranean diets are rich in fruit and vegetables, thereby providing high amounts of plant bioactives including polyphenols, glucosinolates, and antioxidant vitamins. Furthermore, oily fish which is rich in omega-3 fatty acids is an important part of the Asian (e.g., Japanese) and also of the Mediterranean diets. There are specific plant bioactives which predominantly occur in the Mediterranean (e.g., resveratrol from red wine, hydroxytyrosol, and oleuropein from olive oil) and in the Asian diets (e.g., isoflavones from soybean and epigallocatechin gallate from green tea). Interestingly, when compared to calorie restriction which has been repeatedly shown to increase healthspan, these polyphenols activate similar molecular targets such as Sirt1. We suggest that a so-called “MediterrAsian” diet combining sirtuin-activating foods (= sirtfoods) of the Asian as well as Mediterranean diet may be a promising dietary strategy in preventing chronic diseases, thereby ensuring health and healthy ageing. Future (human) studies are needed which take the concept suggested here of the MediterrAsian diet into account.

Neuroprotective Properties of Curcumin in Alzheimer’s Disease – Merits and Limitations

As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especially dementias such as Alzheimers disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility, poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimers disease, as well as its limitations will be discussed in detail.

Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells.

Ochratoxin A (OTA), a mycotoxin mostly produced by Aspergillus ochraceus and Penicillium verrucosum, is a worldwide contaminant of food and feedstuff. OTA is nephrotoxic and a renal carcinogen in rodents. The underlying molecular and cellular mechanisms by which OTA exhibits its toxicity have yet not been fully clarified. In the present study the effects of ochratoxin A on the activity of redox-regulated transcription factors, antioxidant enzymes, as well as glutathione-S-transferase (GST) have been studied in cultured kidney tubulus cells (LLC-PK1). Confluent LLC-PK1 cells were incubated with increasing concentrations of OTA for 24h. OTA decreased SOD activity and enhanced intracellular levels of reactive oxygen species (ROS) as measured by flow cytometry. Furthermore OTA resulted in a down-regulation of GST mRNA and activity levels. Lower GST levels were accompanied by a decreased transactivation of activator protein-1 (AP-1) and NF-E2-related factor-2 (Nrf2), which mediate GST gene transcription. Present data indicate that enhanced ROS production and an impairment of GST activity, possibly due to an AP-1 and Nrf2 dependent signal transduction pathway, may be centrally involved in OTA induced nephrotoxicity.

Effect of dietary quercetin on brain quercetin levels and the expression of antioxidant and Alzheimer's disease relevant genes in mice

The aim of the present feeding trial was to investigate the effect of the dietary flavonol quercetin on brain quercetin concentration and the expression of antioxidant and Alzheimers disease relevant genes in mouse brain. Laboratory mice were fed control and quercetin-enriched diets (2 mg/g diet) for 6 weeks. Dietary quercetin supplementation significantly increased the levels of quercetin and its methylated metabolite isorhamnetin in plasma and brain. However, quercetin and isorhamnetin levels in the brain were manifold lower as compared to the plasma. Both mRNA and activity levels of alpha- and beta-secretase in cortex remained unchanged by the dietary quercetin supplementation. Furthermore dietary quercetin did not affect brain mRNA levels of neprilysin, heme oxygenase-1 and gamma-glutamylcysteine synthetase. Taken together, a short term dietary treatment with quercetin increased quercetin and isorhamnetin levels in the brain but had no effect on mRNA levels of antioxidant and Alzheimers disease relevant genes in mouse brain.

APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans

The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimers disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE ε4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.—Huebbe, P., Nebel, A., Siegert, S., Moehring, J., Boesch‐Saadatmandi, C., Most, E., Pallauf, J., Egert, S., Müller, M. J., Schreiber, S., Nöthlings, U., Rimbach, G. APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J. 25, 3262‐3270 (2011). www.fasebj.org

Differential effects of apolipoprotein E3 and E4 on markers of oxidative status in macrophages

ApoE is secreted by macrophages at the lesion site of the atherosclerotic plaque, where it is thought to play a protective role against atherosclerosis independently of its effects on lipid metabolism. Of the three common isoforms for apoE, apoE4 is associated with higher risk of cardiovascular disease (CVD). In vitro studies have shown that recombinant apoE may act as an antioxidant in an isoform-dependent manner (E2 > E3 > E4). The oxidative status of the macrophages plays a key role in the process of atherosclerosis. In the present study the possible differential actions of apoE3 and apoE4 on several parameters of oxidative status were determined in stably transfected murine macrophages (RAW 264-7-apoE3 and - apoE4). No differences between genotypes were observed after peroxide challenge in either protection against cytotoxicity or in cell membrane oxidation, and modest differences were observed in the non-enzymatic antioxidants (glutathione and alpha-tocopherol) in apoE3 v. apoE4 macrophages. Importantly, cells secreting apoE4 showed increased membrane oxidation under basal conditions, and produced more NO and superoxide anion radicals than the apoE3 macrophages after stimulation. The present data suggest that apoE genotype influences the oxidative status of macrophages, and this could partly contribute to the higher CVD risk observed in apoE4 carriers.

Effects of blackcurrant-based juice on atherosclerosis-related biomarkers in cultured macrophages and in human subjects after consumption of a high-energy meal

Regular consumption of fruit and vegetables may be associated with decreased CVD risk. In the present study, we investigated the effects of blackcurrant (BC) juice, rich in polyphenols and ascorbic acid, on oxidative and inflammatory biomarkers in cultured macrophages in vitro and in human subjects with an atherosclerosis-prone phenotype (after consumption of a high-energy meal). In cultured macrophages (RAW264.7), BC treatment significantly inhibited lipopolysaccharide-induced inflammation as indicated by lower mRNA levels of TNF-α, IL-1β and inducible NO synthase (iNOS) and lower nuclear p65 levels indicating decreased NF-κB activity. iNOS protein levels were lower and haem oxygenase 1 levels higher in BC-treated cells when compared with untreated controls. Subjects given a high-energy meal had elevated serum glucose and insulin levels with no significant difference between the BC-based juice and placebo treatment groups. TAG following meal ingestion tended to be attenuated after the BC treatment. Plasma ascorbic acid and radical-scavenging capacity were decreased following placebo meal consumption; however, BC significantly elevated both parameters compared with baseline and placebo ingestion. Plasma oxidised LDL, α-tocopherol and paraoxonase activity were unchanged in both treatment groups. Furthermore, production of TNF-α and IL-1β was not significantly changed by BC meal consumption. The present results suggest potential antioxidative and anti-inflammatory properties of BC in vitro in cultured macrophages. Although the observations were not directly transferable to a postprandial in vivo situation, the present results show that BC juice consumption may improve postprandial antioxidant status as indicated by higher ascorbic acid levels and free radical-scavenging capacity in plasma.

ApoE genotype: from geographic distribution to function and responsiveness to dietary factors.

ApoE is a key protein in lipid metabolism with three major isoforms. ApoE allele frequencies show non-random global distribution especially in Europe with high apoE ε3 frequency in the Mediterranean area, whereas the apoE ε4 genotype is enriched in Northern Europe. The apoE ε4 genotype is one of the most important genetic risk factors for age-dependent chronic diseases, including CVD and Alzheimers disease (AD). The apoE polymorphism has been shown to impact on blood lipids, biomarkers of oxidative stress and chronic inflammation, which all may contribute to the isoform-dependent disease risk. Studies in mice and human subjects indicate that the apoE ε3 but not the apoE ε4 genotype may significantly benefit from dietary flavonoids (e.g. quercetin) and n-3 fatty acids. Metabolism of lipid soluble vitamins E and D is likewise differentially affected by the apoE genotype. Epidemiological and experimental evidence suggest a better vitamin D status in apoE ε4 than ε3 subjects indicating a certain advantage of ε4 over ε3. The present review aims at evaluation of current data available on interactions between apoE polymorphism and dietary responsiveness to flavonoids, fat soluble vitamins and n-3 fatty acids. Likewise, distinct geographic distribution and chronic disease risk of the different apoE isoforms are addressed.

Implications of apolipoprotein E genotype on inflammation and vitamin E status

In Western societies the apolipoprotein E4 (apoE4) genotype is associated with increased morbidity and mortality and represents a significant risk factor for cardiovascular and Alzheimers disease. In a recent study we observed significantly lower tissue alpha-tocopherol (alpha-TOH) concentrations in apoE4 compared with apoE3 mice. Furthermore, genes encoding for proteins involved in peripheral alpha-TOH transport and degradation were affected by the apoE genotype. Thus, the apoE4 genotype may be associated with lower vitamin E retention in peripheral tissues. This is possibly related to an altered lipoprotein metabolism including increased alpha-TOH retention in LDL, a decreased expression of lipoprotein receptors and impaired cellular vitamin E delivery system, and a greater intracellular degradation of tocopherols in the apoE4 genotype. An increasing number of studies in cultured cells, transgenic mice and human volunteers indicate a more pro-inflammatory state associated with the apoE4 allele. In apoE4 macrophages there is an enhanced transactivation of the key redox sensitive transcription factor NF-kappaB accompanied by a higher production of pro-inflammatory molecules (tumor necrosis factor alpha, interleukin 1beta, macrophage inflammatory protein 1-alpha) and a lower production of anti-inflammatory interleukin 10, as compared with apoE3 macrophages. Both tissue vitamin E retention and biomarkers of chronic inflammation may be affected by the apoE genotype.