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Author Spotlight: Investigating Physiological Functions of Vitamin A Transporters Using HPLC-Based Vitamin A Profiling
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Post-natal all-trans-retinoic acid biosynthesis.

Joseph L Napoli1

  • 1Graduate Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA, United States.

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|May 4, 2020
PubMed
Summary

All-trans-retinoic acid (ATRA) is synthesized from vitamin A via a complex cellular pathway involving specific proteins and enzymes. Understanding this vitamin A metabolism is crucial for preventing diseases linked to its deficiencies or excesses.

Keywords:
Binding-proteinCytochrome P-450Retinal dehydrogenaseRetinoic acidRetinolShort-chain dehydrogenase reductase

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cellular Metabolism
  • Retinoid Signaling Pathways

Background:

  • All-trans-retinoic acid (ATRA), a crucial autacoid derived from vitamin A (retinol), is synthesized through a sophisticated cellular metabolon.
  • This metabolon involves retinol-binding proteins and a network of short-chain dehydrogenase/reductase and aldehyde dehydrogenase enzymes.
  • Cellular uptake and intracellular trafficking of retinol are mediated by specific receptors and binding proteins, including serum retinol-binding protein, Stra6, Rbpr2, and cellular retinol-binding protein 1 (Crbp1).

Purpose of the Study:

  • To elucidate the intricate molecular mechanisms governing the biosynthesis and regulation of all-trans-retinoic acid (ATRA) from vitamin A.
  • To highlight the roles of key proteins and enzymes in the retinoid metabolic pathway.
  • To emphasize the physiological consequences of dysregulated ATRA metabolism, including its hormetic effects and links to various diseases.

Main Methods:

  • The study describes the biochemical pathway of ATRA generation, detailing the enzymes and protein interactions involved.
  • It outlines the transport of retinol from the blood into cells and its subsequent metabolism.
  • The research details the enzymes responsible for retinol oxidation to retinal and further dehydrogenation to ATRA, as well as reductases that convert retinal back to retinol.

Main Results:

  • Serum retinol-binding protein delivers retinol to cells via Stra6 and Rbpr2, facilitating its entry into the Crbp1-mediated pathway.
  • Cellular retinol-binding protein 1 (Crbp1) plays a central role, interacting with lecithin: retinol acyl transferase (Lrat) for esterification and storage, and channeling retinol to dehydrogenases for ATRA synthesis.
  • The balance between esterification and hydrolysis, regulated by the apo-Crbp1/holo-Crbp1 ratio, controls retinol flux. Multiple enzymes catalyze retinol oxidation and retinal reduction, while specific retinal dehydrogenases (Raldh1, 2, 3) irreversibly produce ATRA.

Conclusions:

  • ATRA self-regulates its concentration by inducing Lrat and degradative enzymes, exhibiting hormesis where effects are concentration-dependent.
  • Distorted understanding of ATRA's physiological effects arises from studies using animal models with altered ATRA levels.
  • Mutations or deficiencies in Crbp1 and retinoid-metabolizing enzymes are linked to significant health issues, including cancer, immune deficiency, and metabolic abnormalities.