# Function and Regulation of SLC13A5 in the Liver

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $297,413

## Abstract

Project Summary
 Citrate is a key energy sensor that plays a central role in carbohydrate metabolism, energy production, and
histone acetylation. The intracellular level of citrate is tightly controlled through a balance of biosynthesis and
transport. In the liver, the solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter,
is essential for the import of citrate from the circulation to hepatocytes, a process that can be perturbed by both
xenobiotic and endobiotic stimuli. Recent studies have shown that expression of SLC13A5 was increased in
obese, non-alcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-treated rhesus monkeys, and in
xenobiotic-treated human and rat hepatocytes, suggesting upregulation of SLC13A5 can be a risk factor for
metabolic disorders. In contrast, deletion of SLC13A5 protects mice from HFD-induced hepatic steatosis and
mutations of the SLC13A5 ortholog in D. melanogaster promote longevity. However, despite the emerging
importance of SLC13A5 in energy homeostasis, the mechanism(s) by which the SLC13A5 gene is
transcriptionally regulated and whether clinically used drugs disturb the expression of this transporter are not
well characterized. Moreover, whether SLC13A5 affects hepatic functions beyond lipid homeostasis is largely
unknown. The overall objective of this proposal is to understand the molecular mechanisms governing hepatic
SLC13A5 gene expression and to delineate the role of SLC13A5 in human liver cell proliferation. To this end,
we have shown that 1) prototypical activators of the constitutive androstane receptor (CAR) and the pregnane
X receptor (PXR) robustly induce expression of human SLC13A5; 2) knockdown of SLC13A5 attenuates the
proliferation of hepatocellular carcinoma cells; and 3) expression of SLC13A5 is inversely correlated with the
activation of AMPK signaling. Building on these preliminary results, we hypothesize that CAR and PXR are key
regulators of the inductive expression of SLC13A5 in the liver, and SLC13A5 functions as a nutrient regulator
altering the proliferation of hepatoma cells by modulating AMPK/mTOR signaling pathways. This central
hypothesis will be tested in the following specific aims: Aim 1. Define the role of CAR and PXR in xenobiotic-
induced expression of SLC13A5; Aim 2. Elucidate the mechanism(s) underlying CAR- and PXR-mediated
induction of SLC13A5; Aim 3. Determine the effects of SLC13A5 on hepatoma cell proliferation. The outcomes
are expected to provide fundamental novel knowledge on the transcriptional regulation of SLC13A5 in the liver,
and to delineate a crucial role of SLC13A5 in bridging energy metabolism with liver cancer progression.

## Key facts

- **NIH application ID:** 10082455
- **Project number:** 5R01GM121550-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Hongbing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $297,413
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10082455

## Citation

> US National Institutes of Health, RePORTER application 10082455, Function and Regulation of SLC13A5 in the Liver (5R01GM121550-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10082455. Licensed CC0.

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