YALE JOURNAL OF BIOLOGY AND MEDICINE 91 (2018), pp.95-103.
                   Review
                   Importance of Nutrients and Nutrient 
                   Metabolism on Human Health
                                   a                      b                          a,*
                   Yiheng Chen , Marek Michalak , and Luis B. Agellon
                   a                                                                            b
                   School of Human Nutrition, McGill University, Ste. Anne de Bellevue, QC, Canada;  Department of Biochemistry, University of 
                   Alberta, Edmonton, AB, Canada
                         Nutrition transition, which includes a change from consumption of traditional to modern diets that feature 
                         high-energy density and low nutrient diversity, is associated with acquired metabolic syndromes. The 
                         human diet is comprised of diverse components which include both nutrients, supplying the raw materials 
                         that drive multiple metabolic processes in every cell of the body, and non-nutrients. These components 
                         and their metabolites can also regulate gene expression and cellular function via a variety of mechanisms. 
                         Some of these components are beneficial while others have toxic effects. Studies have found that persistent 
                         disturbance of nutrient metabolism and/or energy homeostasis, caused by either nutrient deficiency or 
                         excess, induces cellular stress leading to metabolic dysregulation and tissue damage, and eventually to 
                         development of acquired metabolic syndromes. It is now evident that metabolism is influenced by extrinsic 
                         factors (e.g., food, xenobiotics, environment), intrinsic factors (e.g., sex, age, gene variations) as well 
                         as host/microbiota interaction, that together modify the risk for developing various acquired metabolic 
                         diseases. It is also becoming apparent that intake of diets with low-energy density but high in nutrient 
                         diversity may be the key to promoting and maintaining optimal health.
                   INTRODUCTION                                                 by changing nutrition practices, health organizations have 
                       Over the last several decades, many jurisdictions  provided dietary recommendations [6]. Whereas past in-
                   around the world have witnessed the increasing preva-        terventions designed to address cases of single nutrient 
                   lence of acquired metabolic syndromes, in particular  deficiencies have achieved clear indicators of success [7], 
                   obesity, diabetes, fatty liver disease and cardiovascular  intervention trials that target a single class of nutrients 
                   diseases [1-4]. In recent years, the upward trend is es-     to manage the emergence of metabolic diseases in the 
                   pecially striking in developing countries where changes      general population have not produced definitive results 
                   in diets and lifestyle accompany modernization [1,5]. To     [8,9]. It is increasingly being realized that comprehensive 
                   counter the increasing public health complications caused    analysis of what is being consumed together with the 
                                                                                eating pattern, rather than focusing on single nutrients, 
                   *To whom all correspondence should be addressed: Luis B. Agellon, McGill University, School of Human Nutrition, 21111 Lakeshore 
                   Road, Ste. Anne de Bellevue, QC H9X 3V9 Canada; Tel: (514) 398-7862; Email: luis.agellon@mcgill.ca.
                   †Abbreviations: mTOR, mechanistic target of rapamycin; ND, nutrient diversity; ED, energy density.
                   Keywords: Cellular stress coping responses, Dietary patterns, Gene function, Metabolism, Metabolic syndromes, Nutrition, Nutrient 
                   diversity 
                    
                   Author Contributions: Yiheng Chen, BSc, prepared a draft of the manuscript; Marek Michalak, PhD, and Luis Agellon, PhD, provided 
                   guidance on topic selection, manuscript outline construction, discussions during the writing process, and editing of the manuscript.
                   Copyright © 2018                                                                                                     95
                    96                                     Chen et al: Nutrients and nutrient metabolism
                    may be more informative in formulating effective dietary         ies have found that the Mediterranean dietary pattern has 
                    recommendations.                                                 preventive and protective effects against cardiovascular 
                         Recent advances in high-throughput analysis have  diseases [16,17], whereas the Western-style dietary pat-
                    assisted in a better understanding of metabolism and re-         tern is positively associated with dyslipidemia, obesity, 
                    vealed the active role of nutrients and their metabolites        hypertension, atherosclerosis, and diabetes [18,19].
                    in regulating gene expression and cellular function. Nu-             Nutrition transition refers to the shift of diet from 
                    trients and their metabolites not only serve as building         traditional to modern along with an increase in sedentary 
                    blocks of cellular structures and as fuel sources, but also      behavior, that occur in conjunction with modernization. 
                    serve as direct modifiers of protein function, potent sig-       The concept of nutrition transition was initially proposed 
                    naling molecules as well as inducers and repressors of  by Popkin [20,21] to demonstrate how economic, demo-
                    gene expression. Many of them participate in regulating          graphic, and epidemiological changes interact with shifts 
                    gene expression by directly modulating the activities  in dietary consumption and energy expenditure. Interest-
                    of transcription factors and by moderating the changes  ingly, some countries in East Asia have lower prevalence 
                    in epigenetic markings in the genome. One view that is           of certain acquired metabolic syndromes compared to 
                    emerging is that optimal cellular homeostasis is crucial         other societies at comparable stages of nutrition transi-
                    for maintaining health and avoiding diseases caused by           tion [2,5,22]. This might be partially due to retention of 
                    nutrient deficiency or excess. In addition, intrinsic factors    traditional dietary patterns, which promote consumption 
                    (e.g., sex, age, gene variations), extrinsic factors (e.g.,      of foods with a wider array of nutrients and lower energy 
                    food, xenobiotics, environment) as well as host/micro-           density [23-25]. However, the reasons underlying the dis-
                    biota  interaction  can  influence  the  assimilation,  trans-   crepancy are complex, and extend beyond the chemical 
                    formation, and action of both nutrients and non-nutrient         composition of food to include social and economic is-
                    components of food. This review considers the impor-             sues. Nevertheless, there is evidence supporting the idea 
                    tance of nutrient diversity and energy density on cellular       that calorie restriction is beneficial for longevity [26-28], 
                    metabolism in health and disease (Figure 1).                     providing support for the potential benefit of low-energy 
                                                                                     density diets (Figure 1A).
                    QUALITY OF NUTRITION                                                 The prevailing global increase in the development of 
                                                                                     acquired metabolic syndromes is associated with nutrition 
                         Single nutrient interventions such as fortification of      transition [29,30]. One proposed concept that potentially 
                    milk with vitamin D, cereal with iron, and table salt with       explains the pathogenesis of these syndromes stems from 
                    iodine were effective in treating the corresponding nutri-       persistent modification of cellular function in response to 
                    ent deficiencies [10]. However, when applied to acquired         stress in the endoplasmic reticulum, mitochondria, and 
                    metabolic syndromes that prevail in modern societies, the        other organelles that make up the cellular reticular net-
                    same approach has yielded inconclusive results [11,12].          work [31]. Both nutrient deficiency (undernutrition) and 
                    For example, decreasing dietary intakes of saturated fatty       nutrient excess (over-nutrition) cause the loss of nutrient/
                    acid or cholesterol, and increasing the intake of omega-3        energy homeostasis and thus trigger cellular stress. Cop-
                    polyunsaturated fatty acids do not appear to be effective        ing response mechanisms, such as the unfolded protein 
                    in reducing the risk of cardiovascular diseases [9,13,14].       response mechanism [31-33], are activated to resolve 
                    The importance of the entire diet that is consumed as a          stress. In the case of a maladaptive response, programmed 
                    regular practice is being recognized, and an increasing  cell death is activated to remove malfunctioning cells. On 
                    number of studies are analyzing dietary pattern to identi-       the other hand, persistent adjustment of cellular functions 
                    fy possible causes of under- and over-nutrition. By defi-        enables cells to cope even with continued exposure to 
                    nition, dietary pattern characterizes the overall diet by the    stress inducers. Stress coping response mechanisms ini-
                    quantities, the proportion, and the variety of foods and         tially promote adaptive strategies to recover homeostasis 
                    beverage as well as the frequency of consumption [15].           in the short term but become pathogenic in the long term 
                    The Mediterranean pattern and Western-style pattern  due to long-term modification of cellular functions.
                    are two commonly practiced dietary patterns. The Med-
                    iterranean diet contains a high proportion of fruits and         FOOD COMPONENTS
                    vegetables, legumes, whole grains, fish, and poultry with 
                    an emphasis on monounsaturated fats and antioxidants,                Food is a complex combination of numerous compo-
                    whereas the Western-style diet is generally characterized        nents which can be classified into nutrients and non-nu-
                    by energy-dense foods like butter, high-fat dairy prod-          trients.  Nutrients  have  been  traditionally  classified  as 
                    ucts, refined grains, as well as processed and red meat,         macronutrients and micronutrients. Plants and animals do 
                    leaving less space for other nutrients especially those  not have identical nutrient requirements and produce nu-
                    coming from fruits and vegetables. Epidemiological stud-         trient metabolites that may not be common to each other. 
                                                          Chen et al: Nutrients and nutrient metabolism                                97
                    Figure 1. Factors that influence human health. A. Relationship of nutrient diversity (ND) and energy density (ED) 
                    in equivalent portion sizes, and their impact on cellular metabolism. B. Extrinsic factors (e.g., food, xenobiotics, 
                    environment), intrinsic factors (e.g., sex, gene variations, age), and host-microbiota interaction work together to 
                    modulate gene expression program, biological processes, and nutrient and energy metabolism.
                    Micronutrients, which include vitamins and minerals, are       is commonly used as a sweetener in commercially pre-
                    needed in only small amounts, and are required for the  pared foods and is present in these foods at exceedingly 
                    proper function of important proteins and enzymes. Mac-        high amounts compared to natural foods [39]. Fructose is 
                    ronutrients, which include carbohydrates, proteins, and  known to stimulate de novo lipid synthesis in the liver and 
                    fats, are typically needed in large amounts. The benefits      to induce endoplasmic reticulum stress in many cell types 
                    of consuming macronutrients are self-evident since their       [40,41]. In general, excess glucose and fructose induce 
                    subunits serve as building blocks of cellular structures  cellular stress which leads to the development of insulin 
                    and as energy substrates in all organisms. Some species        resistance and fatty liver disease [40,42,43]. Certain ami-
                    are unable to synthesize key metabolites needed for  no acids have been shown to act as signaling molecules 
                    survival, and thus must obtain these from other species.       to regulate cellular growth and proliferation via mTOR 
                    These essential metabolites, along with minerals, make  (mechanistic target of rapamycin) [44,45], whose func-
                    up a class of substances referred to as essential nutrients.   tion has been implicated in many human diseases [46]. 
                    Non-nutrient components of food are those that cannot  Some fatty acids from fats and oils serve as ligands for 
                    be categorized as either macronutrients or micronutri-         G protein-coupled receptors as well as for transcription 
                    ents. These substances include both natural and synthetic      factors belonging to the nuclear receptor family of tran-
                    compounds. They can be beneficial (e.g. fiber, and some        scription factors [47,48], and therefore regulate cellular 
                    polyphenolic compounds produced by plants), non-ben-           processes and gene expression [49]. Saturated fatty acids 
                    eficial (e.g. many food additives, and preservatives) or  have long been the focus of investigation as high intake 
                    even toxic (e.g. xenobiotics, and antibiotics, also some  of saturated fats was considered to be a risk factor for 
                    plant-derived polyphenolic compounds) [34,35]. It has  cardiovascular diseases [50], however subsequent studies 
                    become evident that both nutrients and non-nutrients, as       have not provided strong evidence for causality [9]. This 
                    well as their metabolites, have the capacity to modulate       may be partly attributable to the wide range of biologi-
                    gene expression, protein function and epigenome [36-38].       cal activities associated with different fatty acids species 
                        The potential of macronutrients and their metab-           [51]. Palmitic acid, a fatty acid species that is enriched 
                    olites to regulate metabolic function is typically taken  in the Western-style diet, is a potent inducer of endo-
                    for granted. For example, the monosaccharide fructose  plasmic reticulum stress whereas oleic acid, a fatty acid 
                     98                                      Chen et al: Nutrients and nutrient metabolism
                     prominent in the Mediterranean diet, has been shown to             polyphenols on the composition and metabolic activity of 
                     inhibit endoplasmic reticulum stress [52,53]. Importantly,         gut microbiota that provides potential benefits to the host 
                     the surplus of nutrients and energy induce endoplasmic             [68]. Not all polyphenolic compounds are beneficial, as 
                     reticulum stress and inflammatory responses that lead to           some compounds such as caffeic acid and genistein may 
                     systemic metabolic dysregulation [31,32].                          be carcinogenic or genotoxic at high dosage [34,69,70]. 
                          Many metabolic diseases caused by micronutrient  It is commonly assumed that synthetic food additives 
                     deficiencies can be corrected by restoring the missing mi-         (colorants, preservatives, sweeteners) do not have effects 
                     cronutrients in the diet [54,55]. One critical aspect of mi-       on metabolism, but this assumption should be tested 
                     cronutrient supplementation applied to the general popu-           regularly to ensure food safety. Other xenobiotics (e.g. 
                     lation is overdose. Some of these compounds are potent             pollutants,  drugs,  and  agricultural  chemicals)  that  find 
                     modulators of nuclear receptors and have serious impacts           their way into the food supply can influence human health 
                     on the activities of multiple metabolic pathways. For  directly, by disrupting normal metabolic processes, or 
                     example, deficiency of vitamin A can lead to blindness             indirectly, by influencing the composition of the gut mi-
                     while its excess is teratogenic. Vitamin D also modulates          crobiota [71]. All food components likely work together 
                     the expression of many genes that participate in many  to drive metabolic processes in every cell of the body.
                     pathways [56], and its deficiency causes rickets. Howev-
                     er, it is not yet known if it is possible to overdose with this    FACTORS THAT INFLUENCE HUMAN 
                     micronutrient. Excessive dietary intake of minerals can            NUTRITION
                     be  equally  deleterious,  as  exemplified  by  diet-induced 
                     hypertension due to high intake of sodium [57].                         It is now evident that both extrinsic factors (such 
                          Other metabolites produced by the mammalian meta-             as food, xenobiotics, environment) and intrinsic factors 
                     bolic machinery also play critical roles in metabolism. For        (such as sex, age, gene variations), separately and co-
                     example, cholesterol serves as a membrane component,  operatively, influence nutrient metabolism and the risk 
                     signaling molecule, and precursor for the synthesis of  for developing various metabolic diseases (Figure 1B). 
                     steroid hormones and bile acids [58]. Bile acids aid in the        Extrinsic factors are important in dictating the efficiency 
                     absorption of dietary fats and lipid-soluble compounds,            of nutrient metabolism and health outcomes, including 
                     and also act as signaling molecules modulating macro-              physical cues such as photoperiod and temperature. For 
                     nutrient and energy metabolism, inflammatory responses,            example, the alternating light/dark photoperiod of the 
                     and detoxification through intracellular ligand-activated          day-night cycles is important in setting endogenous cir-
                     nuclear receptors [59]. Gut bacteria are capable of metab-         cadian rhythms, which in turn are intimately linked to the 
                     olizing bile acids and one of the products is a secondary          regulation of metabolic activity [72]. Detrimental envi-
                     bile acid referred to as ursodeoxycholic acid. It is of in-        ronments, which include situations that induce the release 
                     terest to note that this bile acid and its taurine-conjugated      of stress hormones, can impair the ability of the body to 
                     derivative can alleviate endoplasmic reticulum stress by           sense and respond to metabolic challenges [73-75]. Ex-
                     promoting proteostasis [60], and has been shown to be              trinsic factors also promote alterations of the epigenome 
                     effective in preventing cardiac fibrosis [61,62].                  which can have long-lasting impacts on nutrient and 
                          The non-nutrient components of food can be benefi-            energy metabolism and contribute to the development of 
                     cial or non-beneficial. Beneficial ones include fiber and          metabolic disorders in organs like the heart (e.g. coronary 
                     certain types of plant polyphenolic compounds. Dietary             heart disease) and the brain (e.g., Alzheimer’s disease) 
                     fiber, derived from plant-based foods, is not an effective         [76-78].
                     nutrient for humans, but serves as a nutrient for gut mi-               Similarly, intrinsic factors such as gene variations, 
                     croflora.  Some of the products generated from dietary             sex, and age, influence the efficiency of nutrient metab-
                     fiber  include  short  chain  fatty  acids  (e.g., butyric and     olism (Figure 1B). Genetic variations impact on the effi-
                     propionic acids) that are absorbed in the lower gut and            cacy of metabolic pathways by affecting the function and 
                     serve as both energy substrates and regulators of host  specific activities of membrane transporters, receptors, 
                     metabolism [63,64]. Plant polyphenolic compounds have              signaling proteins, enzymes, carrier proteins, transcrip-
                     been  popularized  as  anti-oxidants.  However,  there  are        tion factors, and other proteins involved in the transport, 
                     numerous polyphenolic compounds present in plants, and             sensing and processing of specific nutrients [79]. For ex-
                     these compounds likely have a wide range of biological             ample, single nucleotide polymorphisms in genes encod-
                     activities and effects on human metabolism [65,66]. A              ing taste receptors influence food preferences [80]. Varia-
                     polyphenolic-rich extract prepared from potatoes ex-               tions in NPC1L1 cholesterol transporter influence dietary 
                     hibits  beneficial  activity  by  attenuating  weight  gain in     cholesterol absorption [81,82]. Sex and aging determine 
                     mice fed with obesity-inducing high fat diet [67]. There           the biological context and represent important modifiers 
                     is also emerging evidence for the modulating effect of             of metabolic efficiency. Males and females have distinct