# The metabolic basis for impaired bile acid synthesis in malnutrition

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $427,442

## Abstract

Malnutrition contributes to half of all global child deaths. Severe malnutrition interferes with the liver’s synthesis
of albumin, complement and coagulation factors, and bile acids (BAs). BA deficiency impairs nutrient absorption
and growth and alters signaling through nuclear receptors including farnesoid-X-receptor (FXR) to impact a wide
range of processes. Using a mouse model of early postnatal malnutrition, we reported that decreased BA
synthesis in malnutrition causes decreased FXR activation and decreased expression of FXR target genes
including coagulation factors. The resulting malnutrition-induced coagulopathy can cause child mortality. It is
not known why BA synthesis is impaired in malnutrition. Our published data and new preliminary data
indicate malnutrition impairs the activity (not expression) of the rate-determining enzyme (CYP7A1) in the classic
pathway of BA synthesis due to depletion of the essential cofactor heme. We present novel evidence that
restoring heme increases BA synthesis. We now seek to understand why heme synthesis is impaired in
malnutrition. Heme is generated from tricarboxylic acid (TCA) cycle products and enzymes that require iron-
sulfur (Fe-S) clusters for stability. Fe-S clusters are derived from both Fe and S-containing amino acids
(AAs), which are found in dietary protein or generated by transsulfuration. Like most low-protein diets, our mouse
malnourishing diet is deficient in S-containing AAs. The mice exhibit decreased expression of transsulfuration
and Fe-S cluster-dependent TCA cycle enzymes, suggesting that deficiency of S-containing AAs and Fe-S
clusters drives liver dysfunction in malnutrition. Indeed, we decreased BA synthesis by 50% by maintaining
hepatocytes in low-AA media, and we restored BA production by adding S-containing AAs (but not other AAs).
Thus, we hypothesize that deficiency of S-containing AAs in malnutrition impairs BA synthesis by disrupting
TCA cycle function, heme biosynthesis, and CYP7A1 activity. Our Specific Aims are to 1) Characterize in AA-
deficient hepatocytes TCA cycle dysfunction by quantifying flux of labeled glucose through the TCA cycle and
measuring expression levels and activity of Fe-S cluster-dependent TCA cycle enzymes before and after heme
treatment; 2) Define the role of S-containing AAs and heme in BA synthesis by measuring BA synthesis by
hepatocytes maintained in low-AA media and treated in a high-throughput manner with combinations of AAs and
heme and using adeno-associated virus or siRNA to manipulate levels of transsulfuration and Fe-S cluster-
dependent enzymes; and 3) Determine whether a novel nutritional therapeutic can rescue BA synthesis in
malnutrition by feeding mice the malnourishing diet supplemented by S-containing AAs, then quantifying TCA
cycle function, heme synthesis, and BA production in primary hepatocytes. Expected outcomes include
elucidation of a novel link between malnutrition, TCA cycle and heme homeostasis, and BA synthesis.
The r...

## Key facts

- **NIH application ID:** 10501037
- **Project number:** 1R01DK133301-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Geoffrey A Preidis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,442
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501037

## Citation

> US National Institutes of Health, RePORTER application 10501037, The metabolic basis for impaired bile acid synthesis in malnutrition (1R01DK133301-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10501037. Licensed CC0.

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