Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield
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引用次数: 0
Abstract
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalogue of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 non-benign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological IBAT inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal BA excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.