Cystic Fibrosis Liver Disease: Know More

Al-Sinani, Siham; Al-Mulaabed, Sharef; Naamani, Khalid Al; Sultan, Rabab

doi:10.5001/omj.2019.90

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…Furthermore, the bile pH of CF rabbits was lower than that of WT (Fig. 2A ), consistent with the knowledge obtained from CF animal models ( 29 , 30 ) and CF patients ( 28 ). The levels of total serum BAs in the CF rabbits were lower than that in the WT animals (Fig.…”

Section: Resultssupporting

confidence: 89%

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Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit cystic fibrosis transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit non-alcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers. These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment.

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Section: Resultssupporting

confidence: 89%

“…It is known that BA dysregulation contributes to CFLD ( 27 ). One of the first event in CFLD pathogenesis is the reduced bile flow due to the increased bile viscosity ( 28 ). Indeed, the bile from all CF rabbits that were examined ( n = 4, 6 weeks old) was thick and tenacious ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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“…Bile acid (BA) dysregulation contributes to the development of CFLD ( 48 ). BA-targeted metabolomics analysis showed that most BA species were altered in either the bile ( Supplemental Figure 6 ) or liver samples ( Figure 6 ) of the CF rabbits, compared with those of WT animals.…”

Section: Resultsmentioning

confidence: 99%

Sotagliflozin attenuates liver associated disorders in cystic fibrosis rabbits

Liang,

Hou,

Bouhamdan

et al. 2024

JCI Insight

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Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene lead to CF, a life-threating autosomal recessive genetic disease. While recently approved Trikafta dramatically ameliorates CF lung diseases, there is still a lack of effective medicine to treat CF-associated liver disease (CFLD). To address this medical need, we used a recently established CF rabbit model to test whether sotagliflozin, a sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor drug that is approved to treat diabetes, can be repurposed to treat CFLD. Sotagliflozin treatment led to systemic benefits to CF rabbits, evidenced by increased appetite and weight gain as well as prolonged lifespan. For CF liver-related phenotypes, the animals benefited from normalized blood chemistry and bile acid parameters. Furthermore, sotagliflozin alleviated nonalcoholic steatohepatitis–like phenotypes, including liver fibrosis. Intriguingly, sotagliflozin treatment markedly reduced the otherwise elevated endoplasmic reticulum stress responses in the liver and other affected organs of CF rabbits. In summary, our work demonstrates that sotagliflozin attenuates liver disorders in CF rabbits and suggests sotagliflozin as a potential drug to treat CFLD.

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“…Nutritional approaches involve optimizing caloric content up to 150% of estimated daily calories with emphasis on a high fat diet [43] , [44] , dietary supplementation of fat-soluble vitamins and medium chain fatty acids, and pancreatic enzyme supplementation [1] . Protein supplementation can be a balancing act because increased protein in severe CFLD patients can precipitate decompensation [45] . During periods of undernutrition, oral calorie supplements in conjunction with a meal or as a snack between meals [46] can prove vital in rehabilitation.…”

Section: Cfld and General Endocrine Considerationsmentioning

confidence: 99%