GENE EXPRESSION, NUTRIENT REGULATION OF

GENE EXPRESSION, NUTRIENT REGULATION OF. The human genome (or genetic material) is comprised of deoxyribonucleic acid (DNA) that encodes information required for all life processes, including growth, development, reproduction, and even cell death. The functional units within the genome are called genes. Genes are hereditary regions of DNA that encode functional molecules, either proteins or ribonucleic acid (RNA) species. The human genome encodes approximately 100,000 genes on 23 chromosomes. DNA resides in a specific compartment within the cell, known as the nucleus. Each nucleated human cell within an individual, regardless of its origin, contains identical DNA. However, the genetic code is expressed or read differently in each cell type. Gene expression refers to the processes in which the genetic code is deciphered to produce a functional macromolecule, either protein or RNA. While some genes are expressed in all cells, others are expressed exclusively in certain tissues or organs. This selective reading of the code imparts very different chemical, functional, and morphological properties to each cell type and ultimately defines the function of a tissue or organ. Genes can also display temporal specific expression. For example, some genes are expressed only in the fetus, while other genes are not expressed until puberty or adulthood. Therefore, human DNA not only contains all of the genes required to assemble a human organism, but also encodes information that directs where, when, and how much an individual gene will be expressed.

Mechanisms of Gene Expression

Genes encode proteins. Proteins are polymers of amino acid building blocks that serve a variety of biological functions. Proteins can function as intracellular scaffolds that maintain cell integrity; others are transporters that permit specific nutrients and other small molecules to enter the cell. Proteins also can be enzymes that catalyze the many chemical reactions required for cell survival. While DNA is present in the nucleus, protein synthesis occurs in the cytoplasm, a separate compartment within the cell. Therefore, an intermediate molecule is needed to transfer the genetic information from the nuclear compartment that contains the code to the cytoplasmic compartment where the code is read. This intermediate molecule is termed "messenger RNA," and it is a short-lived functional copy of the genetic code. The process by which the genetic code, DNA, is copied to make a messenger RNA molecule occurs in the nucleus and is termed "transcription." The process of reading the genetic code from a messenger RNA molecule occurs in the cytoplasm and is termed "translation." The end product of translation is a protein molecule.

The expression of some genes is predetermined and cannot be altered. However, the expression of other genes, particularly those involved in nutrient storage, processing, and metabolism, is dynamic, and can be influenced by the cell's environment. Therefore, in some instances, gene expression can be an adaptive process. It is now well established that the expression of many genes is, in part, constrained by the nutrient environment—giving credence to the old adage, "you are what you eat." There are more than forty nutrients that are essential for mammals, and deficiencies in any of these nutrients have direct impacts on health. The cellular demand for these nutrients can vary as a function of growth, development, age, reproductive status, and immunity. However, for many organisms, the availability of nutrients can vary daily, weekly, and, in some cases, seasonally without notable changes in health. This is because organisms adapt to nutrient supply by altering gene expression. This alteration, in turn, enables cells to increase their storage capacity for certain nutrients, alter the absorption or excretion of certain nutrients, use alternative metabolic pathways, or reprogram metabolic pathways.

Nutrients as Informational Molecules

If organisms have evolved the ability to reprogram themselves for optimal utilization of the available nutrient resources, then the implication is that a nutrient is not merely a chemical component required for a particular metabolic function, but also that it plays an informational or signaling role in the cell. As with any system that transmits

information, the signal must have a sensor or receiver that can accept, decode, and relay the information that has been transmitted. Cellular proteins that receive and transmit this information are termed "receptors." The receptors then must relay this information via a transducing mechanism to the part of the cell that is capable of reprogramming the cell to adapt to the new environmental conditions. This reprogramming can occur in the cell nucleus or cytoplasm. It can involve changes in the expression of genes (transcription and translation), the stability of messenger RNA and protein, or the activity of proteins. The key principle behind nutrient control of gene expression is specificity. Each receptor must have the capability of binding a nutrient-signaling molecule with specificity and should initiate an adaptive change.

Nutrient Control of RNA Synthesis

The best-understood signaling molecules are hormones such as estrogen and testosterone. A hormone is produced by a particular tissue and causes a specific biological change in the same tissue or a different tissue located elsewhere in the body. In some cases, these molecules can enter a cell and bind to a particular protein molecule, termed a "nuclear receptor." The receptor-hormone complex then travels to the nucleus, binds very specific regions of the DNA, and turns on the expression of genes not normally expressed in the absence of the hormone. This change in gene expression imparts new functional roles to individual cells, which can impact the entire organism greatly. In this manner, diverse biological processes can be initiated, including puberty or menstruation. Certain nutrients can also influence gene expression in a similar manner. Nutrients, including vitamin A, vitamin D, and certain fatty acids, bind nuclear receptors and influence the expression of genes. These nutrient receptors enable cells to sense their nutrient environment and adjust cellular metabolism accordingly by altering the expression of genes.

Nutrient Control of Protein Synthesis

Nuclear receptors are effective in reprogramming DNA transcription to adapt to nutrient environments. Other mechanisms exist to alter gene expression without changing rates of DNA transcription. In fact, alteration of translation is a common mechanism that permits cells to adapt rapidly to changing nutrient environments. Iron is the paradigm for nutrient regulation of gene expression at the level of translation. Iron is a critical component of many metabolic proteins and enzymes involved in oxygen transport, energy metabolism, and DNA synthesis. Iron deficiency results in several disease states, including anemia. Therefore, the body must retain sufficient iron stores to stave off such pathologies. However, iron is also a potent oxidant and, if not bound by proteins in the cell, it can destroy DNA and proteins, and catalyze events that initiate cancer. Therefore, the body must store iron, but in such a manner that prevents the iron from destroying the integrity of its cells. Cells are protected from the deleterious effects of iron by sequestering it in a protein shell called ferritin. Cellular iron is stored in ferritin until required. Ferritin synthesis is rapidly induced when cells are exposed to iron and this increased synthesis is directly regulated by iron. Cells contain an iron-sensing protein called the iron regulatory protein (IRP). This protein binds either iron or ferritin messenger RNA but cannot bind both molecules simultaneously. When iron is not available to the cell, the intracellular concentration of nonprotein-bound iron is very low and IRP does not contain bound iron. This results in IRP being available to bind ferritin messenger RNA, which stops new ferritin synthesis. However, when cells are exposed to iron, IRP contains a bound iron molecule and cannot bind ferritin messenger RNA, and ferritin synthesis occurs. In this manner, the iron storage protein ferritin is only synthesized when it is required to store new iron.

Permanent Adaptation to Nutrient Supply

There is accumulating evidence that prenatal and postnatal nutrition can permanently alter cellular metabolism by altering gene expression throughout adulthood, a phenomenon termed "metabolic imprinting." Low birth weight, which occurred in infants born to survivors of the Dutch Famine of 1944–1945, has been linked to an increased risk of chronic disease later in life, including adult obesity, insulin resistance, hypertension, and cardiovascular disease. The susceptibility to these disease states is influenced both by dietary habits as well as one's genetic predisposition or heritage. Although the biological basis for metabolic imprinting is not yet proven, the suggestion that gene expression can be programmed by fetal and postnatal nutrient environment has far-reaching implications. For many adult chronic disease states, dietary management is an important component of the therapy. If metabolic imprinting occurs, dietary management early in life may also be advantageous in preventing numerous chronic disease states that do not surface until adulthood.

Nutritional Modulation of Gene Expression in Health and Disease

The relationships between nutrient availability and adaptive changes in gene expression are critical to understanding the role of nutrition in health and disease. For many nutrients, either dietary insufficiency or excess can result in or contribute to disease onset. Nutrient modulation of gene expression serves to protect the cell from the deleterious effects of both under-nutrition and over-nutrition. Hereditary hyperferritinemia-cataract syndrome is a human disorder associated with altered regulation of iron homeostasis. Affected individuals have mutations in a ferritin gene that result in the synthesis of a ferritin messenger RNA that encodes a normal functional ferritin protein, but the mutation does not permit IRP to bind to the messenger RNA and stop translation. Therefore, these individuals can no longer regulate ferritin levels in response to changes in iron intake. As a result of this mutation, these individuals contract early-onset bilateral cataract associated with a progressive decrease in visual acuity. Ongoing research is identifying many other nutrient-related disease states that result from disregulation of nutrient control of gene expression.

See also Cholesterol; Combination of Proteins; Genetic Engineering; Genetics; Malnutrition: Protein-Energy Malnutrition; Nutrients; Proteins and Amino Acids .

BIBLIOGRAPHY

Alberts, Bruce, et al. Molecular Biology of the Cell. 3d ed. New York: Garland, 2002.

Allerson, Charles R., M. Cazzola, and Tracey A. Rouault. "Clinical Severity and Thermodynamic Effects of Iron-Responsive Element Mutations in Hereditary Hyperferritinemia-Cataract Syndrome." Journal of Biological Chemistry 274 (1999): 26439–26447.

Berdanier, Carolyn D., and James L. Hargrove. "Nutrient Receptors and Gene Expression." In Nutrition and Gene Expression, edited by Carolyn D. Berdanier and James L. Hargrove. Boca Raton, Fla.: CRC Press, 1993.

Mikulits, Wolfgang, Matthias Schranzhofer, Hartmut Beug, and Ernst W. Müllner. "Post-Transcriptional Control via Iron-Responsive Elements: The Impact of Aberrations in Hereditary Disease." Mutation Research 437 (1999): 219–230.

Repa, Joyce J., and David J. Mangelsdorf. "The Role of Orphan Nuclear Receptors in the Regulation of Cholesterol Homeostasis." Annual Review of Cellular and Developmental Biology 16 (2000): 459–481.

Waterland, Robert A., and Cutberto Garza. "Potential Mechanisms of Metabolic Imprinting that Lead to Chronic Disease." American Journal of Clinical Nutrition 69 (1999): 179–197.

Patrick J. Stover

Familial Hypercholesterolemia

Familial hypercholesterolemia is a disease that results from genetic mutations in the low-density lipoprotein (LDL) receptor. It is one of the most common inborn errors of metabolism. Individuals with one mutated copy of the gene (referred to as heterozygotes for this mutation) number about one in five hundred, whereas one in a million individuals carry two mutated copies of this gene (referred to as homozygotes for a mutation). LDL receptors are necessary for transporting LDL into cells from serum. LDL is a major cholesterol transport lipoprotein in human plasma, and individuals with LDL receptor mutations accumulate LDL in serum because LDL transport into cells is impaired. Plasma cholesterol levels from affected heterozygotes range from 350 to 550 mg/dl, and these values can exceed 1000 mg/dl for affected homozygotes. Individuals with elevated serum cholesterol have a high risk for developing heart disease at very young ages.

Cholesterol is an important component of cell membranes, and it serves to decrease their fluidity. Mammals can synthesize cholesterol in the absence of sufficient dietary cholesterol, but the endogenous biosynthesis is tightly regulated and inhibited by dietary cholesterol supply. A transcription factor known as SREBP (Sterol Response Element Binding Protein) regulates the expression of a gene that encodes a key enzyme that is necessary for cholesterol biosynthesis. When dietary intake of cholesterol is adequate, this transcription factor is sequestered in the membranes of the Golgi compartment of the cell and is inactive. When cellular cholesterol levels fall, however, the membranes in the Golgi become more fluid. This results in the liberation of SREBP from the membrane and enables it to travel to the nucleus, where it can activate the expression of genes that are necessary for cholesterol biosynthesis. Through this regulation, cholesterol biosynthesis occurs only when dietary sources are limited. However, this mechanism of gene regulation fails in familial hypercholesterolemia. Because LDL cholesterol is not effectively transported into cells, the cells cannot sense extracellular cholesterol levels, and therefore cellular SREBP activity and cholesterol biosynthesis is constantly activated. Activated cholesterol biosynthesis serves to further increase serum LDL concentrations in affected individuals.