Annual Review of Nutrition - Volume 22, 2002

Flavonoids comprise the most common group of plant polyphenols and provide much of the flavor and color to fruits and vegetables. More than 5000 different flavonoids have been described. The six major subclasses of flavonoids include the flavones (e.g., apigenin, luteolin), flavonols (e.g., quercetin, myricetin), flavanones (e.g., naringenin, hesperidin), catechins or flavanols (e.g., epicatechin, gallocatechin), anthocyanidins (e.g., cyanidin, pelargonidin), and isoflavones (e.g., genistein, daidzein). Most of the flavonoids present in plants are attached to sugars (glycosides), although occasionally they are found as aglycones. Interest in the possible health benefits of flavonoids has increased owing to their potent antioxidant and free-radical scavenging activities observed in vitro. There is growing evidence from human feeding studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed. However, epidemiologic studies exploring the role of flavonoids in human health have been inconclusive. Some studies support a protective effect of flavonoid consumption in cardiovascular disease and cancer, other studies demonstrate no effect, and a few studies suggest potential harm. Because there are many biological activities attributed to the flavonoids, some of which could be beneficial or detrimental depending on specific circumstances, further studies in both the laboratory and with populations are warranted.

Poor people in developing countries endure the burden of disease caused by four common species of soil-transmitted nematode that inhabit the gastrointestinal tract. Disease accompanying these infections is manifested mainly as nutritional disturbance, with the differing infections having their deleterious effects at different phases during the human life cycle. Reduced food intake, impaired digestion, malabsorption, and poor growth rate are frequently observed in children suffering from ascariasis and trichuriasis. Poor iron status and iron deficiency anemia are the hallmarks of hookworm disease. The course and outcome of pregnancy, growth, and development during childhood and the extent of worker productivity are diminished during hookworm disease. Less is known about the impact of these infections in children under 2 years of age. The severity of disease caused by soil-transmitted nematodes has consistently been found to depend on the number of worms present per person. Cost-effective measures based on highly efficacious anthelminthic drugs are now available to reduce and control disease caused by these infections.

Nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS). As an endothelium-derived relaxing factor, a mediator of immune responses, a neurotransmitter, a cytotoxic free radical, and a signaling molecule, NO plays crucial roles in virtually every cellular and organ function in the body. The discovery of NO synthesis has unified traditionally diverse research areas in nutrition, physiology, immunology, pathology, and neuroscience. Increasing evidence over the past decade shows that many dietary factors, including protein, amino acids, glucose, fructose, cholesterol, fatty acids, vitamins, minerals, phytoestrogens, ethanol, and polyphenols, are either beneficial to health or contribute to the pathogenesis of chronic diseases partially through modulation of NO production by inducible NOS or constitutive NOS. Although most published studies have focused on only a single nutrient and have generated new and exciting knowledge, future studies are necessary to investigate the interactions of dietary factors on NO synthesis and to define the underlying molecular mechanisms.

The urea cycle is comprised of five enzymes but also requires other enzymes and mitochondrial amino acid transporters to function fully. The complete urea cycle is expressed in liver and to a small degree also in enterocytes. However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the “urea cycle” enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is largely transcriptional in virtually all cell types. This review emphasizes recent information regarding roles and regulation of urea cycle and arginine metabolic enzymes in liver and other cell types.

The health benefits of pre- and probiotics have been the subject of increased research interests. These food supplements have been demonstrated to alter the pre-existing intestinal flora so as to provide an advantage to the host. This review focuses on the scientific evidence both for and against their role in promoting health and treating disease. Specific attention is turned to their effects on immunomodulation, lipid metabolism, cancer prevention, diarrhea, Helicobacter pylori, necrotizing enterocolitis, allergy, and inflammatory bowel disease.

Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor involved in the control of metabolism. Research on PPARγ is oriented towards understanding its role in insulin sensitization, which was inspired by the discovery that antidiabetic agents, the thiazolidinediones, were agonists for PPARγ. PPARγ stimulation improves glucose tolerance and insulin sensitivity in type 2 diabetic patients and in animal models of insulin resistance through mechanisms that are incompletely understood. Upon activation, PPARγ heterodimerizes with retinoid X receptor, recruits specific cofactors, and binds to responsive DNA elements, thereby stimulating the transcription of target genes. Because PPARγ is highly enriched in adipose tissue and because of its major role in adipocyte differentiation, it is thought that the effects of PPARγ in adipose tissue are crucial to explain its role in insulin sensitization, but recent studies have highlighted the contribution of other tissues as well. Although relatively potent for their insulin-sensitizing action, currently marketed PPARγ activators have some important undesirable side effects. These concerns led to the discovery of new ligands with potent antidiabetic properties but devoid of certain of these side effects. Data from human genetic studies and from PPARγ heterozygous knockout mice indicate that a reduction in PPARγ activity could paradoxically improve insulin sensitivity. These findings suggest that modulation of PPARγ activity by partial agonists or compounds that affect cofactor recruitment might hold promise for the treatment of insulin resistance.

Investigation of the in vivo kinetics of folate metabolism provides information that contributes to a better understanding of the manner in which this vitamin is processed in vivo. Kinetic studies can yield insight into the requirements for folate, especially with respect to factors that may lead to increased requirements. This review considers the strengths and weaknesses of various approaches to the study of folate kinetics and resulting data, followed by a summary and interpretation of existing data.

Biotin is a water-soluble vitamin required by all organisms by virtue of its essential role in carboxylation reactions. Although the metabolism and role of biotin in intermediary metabolism are well established, biotin remains one of the most poorly understood water-soluble vitamins in terms of nutritional requirements and responsiveness to physiological and pharmacological states. Significant advances in the understanding of biotin nutriture have been recently accomplished through the description of the kinetics and regulation of biotin transport and improved methods for biotin status assessment. Additionally, the potential role of biotin in the regulation of gene expression has been strengthened through description of altered gene expression during biotin deficiency and through newly described enzymatic activities of the enzyme biotinidase. Given mounting evidence of suboptimum biotin status, a more complete understanding of these aspects of biotin should lead to a greater appreciation of the ways in which biotin aids in the maintenance of health.

This paper is an attempt to discuss the problem of malnutrition within the framework of the global need for development and the challenges posed by the trends of neoliberalism and globalization. We argue that there is a two-way link between poverty and health in which nutrition plays an important role both as an active and as a mediating factor. Key concepts are exposed and expanded: (a) Development per se does not ensure better health; (b) unequal distribution of income has an independent effect on health indicators after adjusting for total income; (c) improving health can make an important contribution to reducing poverty; (d ) improving nutrition throughout the whole life course is an indispensable strategy for better health; (e) obesity has to be included amongst the most critical health problems, has different traits, and presents with different challenges in the developing world and in the industrialized countries.

DNA methylation at cytosines in CpG dinucleotides can lead to changes in gene expression and function without altering the primary sequence of the DNA. Methylation can be affected by dietary levels of methyl-donor components, such as folic acid. This may be an important mechanism for environmentally induced changes in gene expression. Recent literature supports a role for DNA-methylation changes in a number of adult-onset disorders and during development. These changes may be significant for better understanding certain birth defects (e.g., neural tube defects) and the long-term consequences of early environmental influences on gene expression (metabolic programming). Optimal “methylation diets” should be investigated as part of the prevention and treatment of all these conditions, as well as in disorders such as Rett syndrome, whose primary defects may lie in DNA methylation-dependent gene regulation.

Humans and other mammals are colonized by a vast, complex, and dynamic consortium of microorganisms. One evolutionary driving force for maintaining this metabolically active microbial society is to salvage energy from nutrients, particularly carbohydrates, that are otherwise nondigestible by the host. Much of our understanding of the molecular mechanisms by which members of the intestinal microbiota degrade complex polysaccharides comes from studies of Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component of the normal human and mouse gut. Colonization of germ-free mice with B. thetaiotaomicron has shown how this anaerobe modifies many aspects of intestinal cellular differentiation/gene expression to benefit both host and microbe. These and other studies underscore the importance of understanding precisely how nutrient metabolism serves to establish and sustain symbiotic relationships between mammals and their bacterial partners.

The progression of the aging process leads to a decreased margin of homeostatic reserve and a reduced ability to accommodate metabolic challenges, including nutritional stress. Nutritional frailty refers to the disability that occurs in old age owing to rapid, unintentional loss of body weight and loss of lean body mass (sarcopenia). Sarcopenia, a loss of muscle mass and strength, contributes to functional impairment. Weight loss is commonly due to a reduction in food intake; its possible etiology includes a host of physiological and nonphysiological causes. The release of cytokines during chronic disease may also be an important determinant of frailty. In addition to being anorectic, cytokines also contribute to lipolysis, muscle protein breakdown, and nitrogen loss. Whereas the multiple causes of nutritional frailty are not completely understood, clinical interventions for weight loss, sarcopenia, and cytokine alterations have been used with modest success.

Skeletal muscle contains the majority of the body's glycogen stores and a similar amount of readily accessible energy as intramyocellular triglyceride (imTG). While a number of factors have been considered to contribute to the pathogenesis of insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM), this review will focus on the potential role of skeletal muscle triglyceride content. In obesity and type 2 DM, there is an increased content of lipid within and around muscle fibers. Changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, almost certainly contribute to accumulation of imTG and to the pathogenesis of both obesity and type 2 DM. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in type 2 DM and obesity, skeletal muscle manifests inflexibility in the transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle appears to be related to the accumulation of imTG and is an important aspect of IR of skeletal muscle in obesity and type 2 DM.

Since the late 1980s, there has been an explosion of information on the molecular mechanisms and functions of vitamin A. This review focuses on the essential role of vitamin A in female reproduction and embryonic development and the metabolism of vitamin A (retinol) that results in these functions. Evidence strongly supports that in situ–generated all-trans retinoic acid (atRA) is the functional form of vitamin A in female reproduction and embryonic development. This is supported by the ability to reverse most reproductive and developmental blocks found in vitamin A deficiency with atRA, the block in embryonic development that occurs in retinaldehyde dehydrogenase type 2 null mutant mice, and the essential roles of the retinoic acid receptors, at least in embryogenesis.

Early studies of embryos from marginally vitamin A–deficient (VAD) pregnant rats revealed a collection of defects called the vitamin A–deficiency syndrome. The manipulation of all-trans retinoic acid (atRA) levels in the diet of VAD female rats undergoing a reproduction cycle has proved to be an important new tool in deciphering the points of atRA function in early embryos and has provided a means to generate large numbers of embryos at later stages of development with the vitamin A–deficiency syndrome. The essentiality of the retinoid receptors in mediating the activity of atRA is exemplified by the many compound null mutant embryos that now recapitulate both the original vitamin A–deficiency syndrome and exhibit a host of new defects, many of which can also be observed in the VAD-atRA-supported rat embryo model and in retinaldehyde dehydrogenase type 2 (RALDH2) mutant mice. A major task for the future is to elucidate the atRA-dependent pathways that are normally operational in vitamin A–sufficient animals and that are perturbed in deficiency, thus leading to the characteristic VAD phenotypes described above.

Long-chain fatty acids are an important constituent of the diet and they contribute to a multitude of cellular pathways and functions. Uptake of long-chain fatty acids across plasma membranes is the first step in fatty acid utilization, and recent evidence supports an important regulatory role for this process. Although uptake of fatty acids involves two components, passive diffusion through the lipid bilayer and protein-facilitated transfer, the latter component appears to play the major role in mediating uptake by key tissues. Identification of several proteins as fatty acid transporters, and emerging evidence from genetically altered animal models for some of these proteins, has contributed significant insight towards understanding the limiting role of transport in the regulation of fatty acid utilization. We are also beginning to better appreciate how disturbances in fatty acid utilization influence general metabolism and contribute to metabolic pathology.

The anorexia of aging is a syndrome characterized by unexplained losses in food intake and body weight that occur near the end of life. Proposed etiologies cover a wide range of biological and psychological conditions. The observation of this phenomenon in older laboratory animals suggests that physiological changes play a significant causal role. Research on the neurochemical control of energy balance has received much attention in recent years, and age-related alterations in the neuropeptidergic effectors of food intake have been implicated in the anorexia of aging. This review provides an update on putative mechanisms underlying this dysregulation of feeding during advanced age.

Ceruloplasmin is a serum ferroxidase that contains greater than 95% of the copper found in plasma. This protein is a member of the multicopper oxidase family, an evolutionarily conserved group of proteins that utilize copper to couple substrate oxidation with the four-electron reduction of oxygen to water. Despite the need for copper in ceruloplasmin function, this protein plays no essential role in the transport or metabolism of this metal. Aceruloplasminemia is a neurodegenerative disease resulting from inherited loss-of-function mutations in the ceruloplasmin gene. Characterization of this disorder revealed a critical physiological role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and has provided new insights into human iron metabolism and nutrition.