# Targeting SGLTs for liver disease in a rabbit model of cystic fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $610,883

## Abstract

PROJECT SUMMARY
Cystic fibrosis (CF)-related liver disease (CFLD) is the third-leading cause of mortality in CF, an autosomal
genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
gene. Approximately 20% to 40% CF patients suffer from CFLD, and the number is on the rise in the past
decade. Of concern, the recently approved Trikafta, although significantly improves the pulmonary functions,
worsens liver related disorders in CF patients, supported by emerging clinical reports. Treating/curing CFLD in
the post-Trikafta era now becomes a top priority research topic. A lack of appropriate preclinical animal models
for CFLD has been a limiting factor for drug development. Recently, we produced CF rabbits and
demonstrated that they manifest many typical CF phenotypes. Importantly, liver phenotypes including
abnormal bile secretion, NASH-like phenotypes, and impaired lipid and glucose homeostasis were observed,
presenting them as a promising model for CFLD and drug testing. Further, we obtained strong preliminary
evidence that treatments of sodium-dependent glucose cotransporter (SGLT) inhibitors (SGLTi) exerted
surprising therapeutic effects on CFLD phenotypes of CF rabbits. Based on these, we hypothesize that “CFTR
mutation -> inflammation & ER stress -> SGLT1 upregulation -> metabolic disorder -> CFLD” form a vicious
circle and that disruption of this circle by SGLTi drugs is beneficial for CFLD. To test this hypothesis, we will
utilize our recently developed CF rabbits carrying the dominant patient mutation CFTR-F508del (dF) to pursue
two specific aims: in Aim 1, we will determine the effects of Trikafta with a focus on the livers of dF rabbits,
followed by experiments to determine if SGLTi drugs, such as Sotagliflozin and Empagliflozin, bring any
benefits to dF rabbit livers on top of Trikafta. In Aim 2, we will investigate the molecular mechanisms by which
SGLT inhibition benefits CF liver disease by determining the effects of SGLTi drugs on the ER stress and
inflammation pathways in dF rabbit livers and in human dF cholangiocytes and hepatocytes. Our work will
provide preclinical and mechanistic evidence for expanding (or not) the use of this class of extraordinary
successful drugs, i.e., SGLT inhibitor drugs, for an unmet medical challenging: CFLD in the post-Trikafta era.

## Key facts

- **NIH application ID:** 10857203
- **Project number:** 5R01DK134361-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JIE XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $610,883
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857203

## Citation

> US National Institutes of Health, RePORTER application 10857203, Targeting SGLTs for liver disease in a rabbit model of cystic fibrosis (5R01DK134361-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10857203. Licensed CC0.

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