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

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.