Vitamin A An overview on history metabolism and

Vitamin A – An overview on history, metabolism and role in health Catharine Ross, Ph. D. Nutritional Sciences Penn State 3 rd International Vitamins Conference, Hamilton Crowne Plaza, Washington DC, May 12 -15, 2014

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Outline Focus – • Highlights in the history of vitamin A research • Metabolism • Role in Health

Other key discoveries… • 1949 Arens and van Dorp: reported vitamin A acid (retinoic acid) as an active form of vitamin A • 1950 -60 s Wald and coworkers: eludicated the visual cycle and role of rhodopsin in vision. 1967 Nobel Prize in Physiology, to Ragnar Granit, Haldan Keffer Hartline and George Wald "for their discoveries concerning the primary physiological and chemical visual processes in the eye"

Historical reading • Wolf, G. A history of vitamin A and retinoids. FASEB J. 1996; 10: 1102 -7. • Chambon, P. How I became one of the fathers of a superfamily. Nat Med. 2004; 10: 1027 -31. • Semba, R. D. The Vitamin A Story: Lifting the Shadow of Death. Karger, 2012.

II. Metabolism

Ross and Harrison, Handbook of Vitamins, 2014

Retinol is recycled before being degraded In a modeling study with 3 human subjects, “the average 14 C-retinol molecule spent 5. 4 hr in the plasma before leaving reversibly or irreversibly, and recycled to the plasma three times before irreversible utilization occurred. …. The estimated disposal rate (1. 71 mg/day, assuming steady-state conditions) is close to the U. S. RDA for vitamin A, of 1 mg/day. ” (Green MH and Green JB, Dynamics and control of plasma retinol, In: Vitamin A in Health and Disease, R. Blomhoff, ed. , Dekker, 1994. ) In modeling studies – plasma retinol was best predictor of VA irreversible disposal rate (Kelley SK and Green MH, J. Nutr. 1998 128: 1767 -73. )

RBP is a negative acute phase protein Nutrient–Acute Phase Protein Associations Nutrient Copper Protein Carrier Ceruloplasmin Nutrient Vitamin A Metallothionein Iron Ferritin Haptoglobin Heptacidin Hemopexin Zinc Albumin Metallothionein Selenium Selenoprotein P Carrier Retinol-Binding Transthyretin Vitamin B 12 Transcobalamin Vitamin D Gc globulin (DBP)

INSPIRE Project Inflammation & Nutritional Science for Programs/Policies: Interpretation of Research Evidence Workshop, Oct 2012, 80 participants Overview: General Principles of Immunology and Inflammation Theme 2 B: Impact of inflammation on nutrition Theme 1: Overview of the role of nutrition in immune function and the inflammatory response Theme 3: Translating Evidence to Practice: approach to addressing nutrition and inflammation Theme 2: Nutrition and Inflammation 2 A: Impact of nutrition on the immune response Theme 4: New Technologies and methodologies GOALS: Each theme group will produce a manuscript to be submitted to Journal of Nutrition, which will then be put on the BOND/INSPIRE website for guidance and use.

III. Health Effects of Vitamin A Vision Gene expression and cell differentiation -- Retinal -- Retinoic acid

Retinoic acid as a developmental regulator • Since 1930 s • Too much and too little VA are both teratogenic. • RA itself has potent effects on organ and limb development – Organogenesis—neural tube/somites, heart, eyes, lungs, limbs – Limb specification during embryogenesis – Limb regeneration in adult amphibians and zebrafish – Lung septation in postnatal rats, mice – Lung regeneration in some models

More recently described functions and potential uses in health • Immune system regulator • Stimulus for postnatal lung development and repair • As a regulator of metabolism?

In summary - • Vitamin A has had an exceptional first 100 years. • Vitamin A’s metabolism is directed by chaperone proteins and enzymes that help to regulate the production and catabolism of retinal and retinoic acid. • Vitamin A is well recognized as an essential nutritional factor for development and for maintaining homeostasis. • Vitamin A is part of the WHO Millenium Development Goals, namely for improving survival and health of children under 5 y. • The health effects of vitamin A are widespread – vision, skin health, and immune system, with new possibilities for stem cell differentiation and tissue repair.