Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Montefusco, David; Jamil, Maryam; Maczis, Melissa A.; Schroeder, W. J.; Levi, Moshe; Ranjit, Suman; Allegood, Jeremy C.; Bandyopadhyay, Dipankar; Retnam, Reuben; Spiegel, Sarah; Cowart, L. Ashley

doi:10.1016/j.molmet.2022.101523

Cited by 9 publications

(6 citation statements)

References 82 publications

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“…41 However, mechanistic studies suggest that estrogen may have a protective effect in fibrogenesis. 42,43 For PNFI, the data included in our cohort revealed the inability to replicate the performance recently reported by Mosca et al 27 For the detection of moderate fibrosis, the highest AUROC of 0.697 was afforded by APRI, which was comparable to previous studies. 24,27 Yet, diagnostic utility of APRI was rendered insufficient by low test sensitivity.…”

Section: Noninvasive Fibrosis Scoressupporting

confidence: 44%

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Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease

Kalveram,

Baumann,

De Bruyne

et al. 2023

J. pediatr. gastroenterol. nutr.

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ObjectivesNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of pediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of pediatric patients with NAFLD.MethodsThe 457 patients with biopsy‐proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB‐4), pediatric NAFLD fibrosis score (PNFS) and pediatric NAFLD fibrosis index (PNFI).ResultsPatients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB‐4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB‐4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut‐off.ConclusionsEstablished fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk‐stratification in pediatric NAFLD.

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Section: Noninvasive Fibrosis Scoressupporting

confidence: 44%

“…Sex differences in the development of fibrosis in patients with NAFLD have not been reported before in paediatric studies and remained inconclusive in adult patients 41 . However, mechanistic studies suggest that estrogen may have a protective effect in fibrogenesis 42,43 …”

Section: Discussionmentioning

confidence: 99%

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease

Kalveram,

Baumann,

De Bruyne

et al. 2023

J. pediatr. gastroenterol. nutr.

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“…Next, it was of interest to examine the mechanism by which Ormdl3 overexpression induced sex differences in the development of diet-induced non-alcoholic fatty liver disease and steatohepatitis in mice. Similar to white adipose tissue, sex differences in livers from ORMDL3 TG mice were observed in sphingolipid metabolites S1P and C16:0 ceramide, which are known to be involved in the pathogenesis of obesity, insulin resistance, and the development of NASH [ 6 , 8 , 9 , 12 , 13 , 33 , 35 , 37 , 42 ]. Whereas Ormdl3 overexpression increased S1P and C16:0 ceramide in male mice, it reduced them in female mice ( Figure 7 A).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis

Brown,

Green,

Weigel

et al. 2024

Molecular Metabolism

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“…C57BL/6 wild-type mice were from The Jackson Laboratory. Mouse strains used were Eln(+/-) ( 10 ), Acta2-GFP ( 22 ), Acta2-CreER T2 ( 63 ), Cdh5-CreER T2 ( 64 ) , Sphk1(flox/flox) ( 65 ), S1pr1(knock-in/knock-in) ( 32 ), and H2B-GFP ( 32 ). Mice were bred, and embryos or pups were harvested at different ages with embryonic day (E) 0.5 considered noon of the day that the vaginal plug was detected.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization

Saito,

Dave,

Gallardo-Vara

et al. 2024

Preprint

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Defective elastin and smooth muscle cell (SMC) accumulation characterize both arterial diseases (e.g., atherosclerosis, restenosis and supravalvular aortic stenosis [SVAS]), and physiological ductus arteriosus (DA) closure. Elastin deficiency induces SMC hyperproliferation; however, mechanisms underlying this effect are not well elucidated. Elastin (ELN) is expressed from embryonic day (E) 14 in the mouse aorta. Immunostains ofEln(+/+)andEln(-/-)aortas indicate that SMCs of theElnnull aorta are first hyperproliferative at E15.5, prior to morphological differences. Bulk RNA-seq reveals that sphingosine kinase 1 (Sphk1) is the most upregulated transcript inEln(-/-)aortic SMCs at E15.5. Reduced ELN increases levels of transcription factor early growth response 1 (EGR1), resulting in increased SPHK1 levels in cultured human aortic SMCs and in the mouse aorta at E15.5 and P0.5. Aortic tissue from Williams-Beuren Syndrome patients, who have elastin insufficiency and SVAS, also has upregulated SPHK1 expression. SMC-specificSphk1deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease, leading to extended survival ofEln(-/-)mice. In addition, EGR1 and SPHK1 are increased in the wild-type mouse DA compared to adjacent descending aorta. Treatment with a SPHK1 inhibitor attenuates SMC proliferation and reduces SMC accumulation, leading to DA patency. In sum, SPHK1 is a key node in elastin deficiency-induced hypermuscularization, and inhibiting this kinase may be a therapeutic strategy for SVAS and select congenital heart diseases in which a patent DA maintains circulation.One Sentence SummarySphingosine kinase 1-induced by defective elastin promotes muscularization in pathological aortic stenosis and physiological ductus arteriosus occlusion.

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Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Cited by 9 publications

References 82 publications

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease

Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis

Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization

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