Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

Physiological and molecular basis of thyroid hormone action.

The hypothesis that plasma chylomicrons in persons who ingest a cholesterol-rich diet are atherogenic is evaluated. Evidence is presented that in humans, and experimental animals, chylomicron remnants as well as low-density lipoproteins are taken up by arterial cells. In persons who do not have familial hyperlipoproteinemia, atherogenesis may occur during the postprandial period. Research directions that may contribute to the evaluation of chylomicron remnants as a risk factor for atherogenesis are discussed. Lipoprotein studies after administration of a test meal containing fat and cholesterol are urgently needed.

Atherogenesis: a postprandial phenomenon.

Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells

This book on vitamin A deficiency not only addresses ocular manifestations but also the broader context of child health and survival. The introduction examines the historical and modern perspectives of vitamin deficiency what vitamin A is and the relationship of xerophthalmia (severe vitamin A deficiency) to vitamin A status. The second section of the book discusses consequences of vitamin A deficiency. Chapter 2 looks at mortality associated with moderate to severe deficiency and the fact that vitamin A supplementation reduces preschool-age mortality and measles mortality. Chapter 3 covers infectious morbidity particularly diarrhea measles respiratory disease urinary tract infection otitis and other infections (e.g. HIV). Chapter 4 examines ocular manifestations (xerophthalmia keratomalacia night blindness and conjunctiva). The effect of vitamin A on anemia and iron metabolism and the extent of vitamin A deficiency-associated anemia are discussed in chapter 5. Chapter 6 examines vitamin As role in growth in animals and children. The third section of the book is dedicated to mechanisms of vitamin A. Chapter 7 looks at contributory and precipitating events (i.e. systemic infections and protein energy malnutrition). Chapter 8 addresses the biochemistry of vitamin A and carotenoids. Chapter 9 examines the relationship between immunocompetence and vitamin A status particularly lymphoid organs and hematopoiesis cell-mediated immunity humoral immunity effect of vitamin A administration on immune response and identification of and requirements for immunoregulatory retinoids. The fourth section chapter 10 is dedicated to treatment of vitamin A deficiency and xerophthalmia. The last section covers assessment and prevention. Chapters 11 and 12 discuss assessment of vitamin A status and epidemiology of deficiency respectively. The last three chapters examine prevention interventions: dietary interventions supplementation and fortification of dietary items with vitamin A.

Vitamin A Deficiency: Health, Survival, and Vision

Researchers affiliated with the International Nutrition Program at the University of Toronto reviewed 20 trials of vitamin A and morbidity and 10 trials of vitamin A and young child mortality to determine the effectiveness of vitamin A supplementation on reducing mortality and morbidity in children from developing countries. All the populations were characterized by general poverty high prevalence of stunting and clinical manifestations of vitamin A deficiency sufficiently prevalent to be considered a public health problem. The analysis using the random effect model confirmed that vitamin A supplementation does indeed reduce mortality rates in young children (by about 23%) (relative risk = 0.77 confidence interval = 0.68-0.88; p < 0.001). The 10 trials reported reductions in mortality associated with vitamin A supplementation ranging from 0 to 50%. Vitamin A supplementation reduced mortality rates regardless of gender and age between 6 months and 5 years. It had clear effects on mortality linked to diarrhea and measles. It apparently had no effect on mortality linked to respiratory infections and malaria. None of the mortality studies included children with biochemical evidence of vitamin A depletion with associated evidence of at least a low prevalence of xerophthalmia. The effect of vitamin A supplementation on morbidity is less clear than its effect on mortality. Vitamin A supplementation does not appear to improve general morbidity but does have a beneficial effect on severe morbidity. In the case of measles the evidence suggests that even after the onset of infection vitamin A supplementation can improve the course of the episode and the case fatality rate. In conclusion vitamin A probably has more of an effect on the processes linked to response to infection than to those linked to resistance to infection.

Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries

Regulation of Retinol-binding Protein Metabolism by Vitamin A Status in the Rat

The subcellular compartments have been investigated to compare proteins capable of binding triiodothyronine and thyroxine; specific binders have been found in cytosol, nuclei, and mitochondria from rat liver and kidney. The binding protein from the inner mitochondrial membrane had the highest association constant (greater than 10(11) liters per mole), suggesting possible direct hormone action on the mitochondria. Binding of hormone analogs was found to be related to known physiological potency, and stereospecific discrimination between L- and D-thyroxine was observed. The saturable receptor was found in the mitochondrial membranes of rat liver, kidney, myocardium, and skeletal muscle but not in mitochondria from the unresponsive tissues: brain, spleen, and testis. Oxidative phosphorylation by mitochondrial vesicles from hypothyroid rats increased after the addition of physiological concentrations of triiodothyronine, which corroborated direct hormone action on mitochondria.

Thyroid hormone action: the mitochondrial pathway.

The transport of retinoic acid in plasma was examined in vitamin A-deficient rats maintained on small doses of radioactively labelled retinoic acid. After ultracentrifugation of serum adjusted to density 1.21, most of the radioactivity (83%) was associated with the proteins of density greater than 1.21, and not with the serum lipoproteins. Gel filtration of the labelled serum on Sephadex G-200 showed that the radioactive label was associated with protein in the molecular-weight range of serum albumin. On polyacrylamide-gel electrophoresis almost all of the recovered radioactivity migrated with serum albumin. Similar esults were obtained with serum from a normal control rat given a single oral dose of [14C]retinoic acid. These findings indicate that retinoic acid is transported in rat serum bound to serum albumin, and not by retinol-binding protein (the specific transport protein for plasma retinol). Several tissues and the entire remaining carcase of each rat were extracted with ethanol–acetone to determine the tissue distribution of retinoic acid and some of its metabolites. The total recover of radioactive compounds in in the entire body of the rat was about 7–9μg, representing less than 5% or 10% respectively of the total administered label in the two dosage groups studied. The results confirm that retinoic acid is not stored in any tissue. Most of the radioactive material was found in the carcase, rather than in the specific tissues analysed. Two-thirds of the radioactivity in the carcase appeared to represent unchanged retinoic acid. Of the tissues examined, the liver, kidneys and intestine had relatively high concentrations of radioactive compounds, whereas the testes and fat-pads had the lowest concentrations.

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The plasma transport and metabolism of retinoic acid in the rat.

Binding studies of thyroid hormone to submitochondrial fractions from rat liver suggest that the component responsible for high-affinity, low-capacity (saturable) binding of hormones arises from the inner mitochondrial membrane. The partially purified component, approximately 150,000 daltons, appears to be half protein and half lipid, largely phospholipids, tentatively identified as lecithin, phosphatidyl ethanolamine, and cardiolipin. A similar hormone-binding macromolecule was found in mitochondria from rabbit kidney, from human liver and kidney, and from rat kidney, myocardium, skeletal muscle, intestinal mucosa, whole small intestine, adipose tissue, and lung. It was absent from mitochondria of adult rat brain, spleen, and testis, organs calorigenically unresponsive to thyroid hormones injected in vivo, but was present in mitochondria from brains of rats 12 days old and younger. The organ distribution of the hormone-binding protein and its presence in neonatal brain mitochondria supports the biological relevance of the mitochondrial component as a thyroid hormone receptor.

https://science.sciencemag.org/content/sci/201/4361/1126.full.pdf

Mitochondrial thyroid hormone receptor: localization and physiological significance.

The thyroid hormone, triiodothyronine, has been shown to be bound by the intranuclear chromatin protein associated with active DNA, where it is believed to stimulate transcription. Evidence exists that the thyroid hormones have direct action not only on nuclei, but also on mitochondria. Threfore, specific proteins that bind thyroid hormones in the mitochondria should be demonstrable. Mitochondria were isolated from homogenized rat livers by sedimentation through 0.25 M sucrose solution, followed by washing four times to free them of microsomes. Strong binding of thyroid hormones was observed in mitochondrial fractions prepared from both the membranes and the matrix. After incubation in an ice bath with increasing amonts of triiodothyronine with added tracer [125I]triiodothyronine, the matrix infrequently contained specific saturable receptor sites, but usually exhibited strong "nonspecific" interaction...

https://www.pnas.org/content/pnas/72/8/3225.full.pdf

Peter O. Milch

Papers

Regulation of Retinol-binding Protein Metabolism by Vitamin A Status in the Rat

Thyroid hormone action: the mitochondrial pathway.

The plasma transport and metabolism of retinoic acid in the rat.

Mitochondrial thyroid hormone receptor: localization and physiological significance.

Thyroid hormone binding by a component of mitochondrial membrane