# Mechanism of Selenoprotein Synthesis

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2020 · $463,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Selenium (Se) is an essential trace element long known for its antioxidant properties, most or all of which are
attributable to selenoproteins. Selenoproteins function in all aspects of life, from early development through
diseases associated with aging, and most of the biological processes in between. Considerable progress has
been made in our understanding of how Se is incorporated into selenoproteins, but major gaps in our
knowledge remain, including how Se is preferentially retained and utilized in crucial tissues when the trace
element is limiting. Selenocysteine is recycled in the body via selenocysteine lyase (Scly). Targeted disruption
of the Scly gene in mice results in metabolic syndrome, with the phenotype being more pronounced in males
than females. Interestingly, evidence from clinical trials suggests a gender specific effect of the influence of
Se on glucose homeostasis, demonstrating a higher incidence of type 2 diabetes among Se supplemented
men with an adequate Se intake but not among women. Thus, the Scly knockout mouse model may have
direct relevance for the importance of proper Se metabolism in human health. The overall objectives of this
proposal are to elucidate the mechanistic basis for the metabolic syndrome phenotype in response to Scly
knockout, and the reasons underlying the sex-specific nature of this phenotype. The long-term goals of our
research are to understand the underlying molecular, cellular and tissue-specific mechanisms behind the
regulatory pathways governing Se distribution and selenoprotein synthesis. Achievement of these goals will
provide information that is essential to furthering our understanding of how Se is utilized for optimum health.
Our central hypothesis is that Scly functions in tissue- and selenoprotein-specific recycling of selenocysteine,
contributing to mechanisms whereby crucial selenoproteins in specific tissues have priority on Se when the
trace element is limiting. We further hypothesize that impaired synthesis of crucial selenoproteins when Scly
expression is disrupted results in metabolic syndrome. We will address this hypothesis via the following
specific aims: Specific Aim 1: Identify changes in metabolic pathways and selenoprotein gene expression that
occur in male and female mice in response to whole body Scly KO, and which of these are affected by CAST
and/or testosterone (TST)-replacement. Specific Aim 2: Generate and characterize effects of tissue-specific
liver, pancreatic islet and hypothalamic Scly KO in male and female mice, and effects of CAST and TST-
replacement. Specific Aim 3: Establish cell culture models to further investigate which of the changes
identified in aims 1 and 2 contribute to MetS in male versus female Scly KO mice. These studies will provide
new insights into the mechanisms of Se distribution, selenoprotein synthesis, and the functions selenoproteins
and Se recycling in energy metabolism and metabolic syndrome.

## Key facts

- **NIH application ID:** 9892999
- **Project number:** 5R01DK047320-24
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Marla J Berry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,000
- **Award type:** 5
- **Project period:** 1998-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892999

## Citation

> US National Institutes of Health, RePORTER application 9892999, Mechanism of Selenoprotein Synthesis (5R01DK047320-24). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892999. Licensed CC0.

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