المؤلفون: Kozlitina, Julia, Cohen, Naomi M., Sturtevant, Drew, Cohen, Jonathan C., Murphey-Half, Cathi, Saltarrelli, Jerome G., Jindra, Peter, Askar, Medhat, Hwang, Christine S., Vagefi, Parsia A., Lacelle, Chantale, Hobbs, Helen H., MacConmara, Malcolm P.

المساهمون: United Network for Organ Sharing, U.S. Department of Health and Human Services, Health Resources and Services Administration, National Institutes of Health, American Society of Transplant Surgeons

المصدر: eClinicalMedicine ; volume 67, page 102350 ; ISSN 2589-5370

مصطلحات موضوعية: General Medicine

الإتاحة: https://doi.org/10.1016/j.eclinm.2023.102350Test
https://api.elsevier.com/content/article/PII:S2589537023005278?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2589537023005278?httpAccept=text/plainTest

المؤلفون: Sun, Yingyuan, Wang, Jin, Long, Tao, Qi, Xiaofeng, Donnelly, Linda, Elghobashi-Meinhardt, Nadia, Esparza, Leticia, Cohen, Jonathan C., Xie, Xiao-Song, Hobbs, Helen H., Li, Xiaochun

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2021 Aug . 118(34), 1-10.

الوصول الحر: https://www.jstor.org/stable/27075519Test

المؤلفون: Stender, Stefan, Smagris, Eriks, Lauridsen, Bo K, Kofoed, Klaus F, Nordestgaard, Børge G, Tybjærg‐Hansen, Anne, Pennacchio, Len A, Dickel, Diane E, Cohen, Jonathan C, Hobbs, Helen H

المصدر: Hepatology. 67(6)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Adult, Aged, Animals, Female, Genetic Variation, Humans, Liver, Liver Glycogen, Male, Mice, Middle Aged, Protein Phosphatase 1, Triglycerides, Medical Biochemistry and Metabolomics, Gastroenterology & Hepatology, Clinical sciences

الوصف: Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 × 10-5 ), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 × 10-4 ) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC.ConclusionThese observations are consistent with the notion that the minor allele of rs4841132 promotes a mild form of hepatic glycogenosis that is associated with hepatic injury. (Hepatology 2018;67:2182-2195).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6918g7h4Test

المؤلفون: Das, Avash, Cheng, Haili, Wang, Yang, Kinch, Lisa N, Liang, Guosheng, Hong, Sen, Hobbs, Helen H, Cohen, Jonathan C

المصدر: Proc Natl Acad Sci U S A ; ISSN:1091-6490 ; Volume:121 ; Issue:6

مصطلحات موضوعية: hepatocyte, lipid droplets, mutation, steatosis, ubiquitin proteasome system

الوصف: A missense variant in patatin-like phospholipase domain-containing protein 3 [PNPLA3(I148M)] is the most impactful genetic risk factor for fatty liver disease (FLD). We previously showed that PNPLA3 is ubiquitylated and subsequently degraded by proteasomes and autophagosomes and that the PNPLA3(148M) variant interferes with this process. To define the machinery responsible for PNPLA3 turnover, we used small interfering (si)RNAs to inactivate components of the ubiquitin proteasome system. Inactivation of bifunctional apoptosis regulator (BFAR), a membrane-bound E3 ubiquitin ligase, reproducibly increased PNPLA3 levels in two lines of cultured hepatocytes. Conversely, overexpression of BFAR decreased levels of endogenous PNPLA3 in HuH7 cells. BFAR and PNPLA3 co-immunoprecipitated when co-expressed in cells. BFAR promoted ubiquitylation of PNPLA3 in vitro in a reconstitution assay using purified, epitope-tagged recombinant proteins. To confirm that BFAR targets PNPLA3, we inactivated Bfar in mice. Levels of PNPLA3 protein were increased twofold in hepatic lipid droplets of Bfar-/- mice with no associated increase in PNPLA3 mRNA levels. Taken together these data are consistent with a model in which BFAR plays a role in the post-translational degradation of PNPLA3. The identification of BFAR provides a potential target to enhance PNPLA3 turnover and prevent FLD.

العلاقة: https://doi.org/10.1073/pnas.2312291121Test; https://pubmed.ncbi.nlm.nih.gov/38294943Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861911Test/

الإتاحة: https://doi.org/10.1073/pnas.2312291121Test
https://pubmed.ncbi.nlm.nih.gov/38294943Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861911Test/

المؤلفون: Hobbs, Helen H., Cohen, Jonathan C., Horton, Jay D.

المصدر: Circulation ; volume 149, issue 3, page 171-173 ; ISSN 0009-7322 1524-4539

الإتاحة: https://doi.org/10.1161/circulationaha.123.064498Test

المؤلفون: Kubiliun, Maddie J., Cohen, Jonathan C., Hobbs, Helen H., Kozlitina, Julia

المساهمون: National Institute of Diabetes and Digestive and Kidney Diseases

المصدر: Liver International ; volume 42, issue 10, page 2227-2236 ; ISSN 1478-3223 1478-3231

الوصف: Background and aims Susceptibility to fatty liver disease (FLD) varies among individuals and between racial/ethnic groups. Several genetic variants influence FLD risk, but whether these variants explain racial/ethnic differences in FLD prevalence is unclear. We examined the contribution of genetic risk factors to racial/ethnic‐specific differences in FLD. Methods A case–control study comparing FLD patients ( n = 1194) and population‐based controls ( n = 3120) was performed. Patient characteristics, FLD risk variants ( PNPLA3‐ rs738409 + rs6006460, TM6SF2‐ rs58542926, HSD17B13‐ rs80182459 + rs72613567, MBOAT7 / TMC4‐ rs641738, and GCKR‐ rs1260326) and a multi‐locus genetic risk score (GRS) were examined. The odds of FLD for individuals with different risk factor burdens were determined. Results Hispanics and Whites were over‐represented (56% vs. 38% and 36% vs. 29% respectively) and Blacks under‐represented (5% vs. 23%) among FLD patients, compared to the population from which controls were selected ( p < .001). Among cases and controls, Blacks had a lower and Hispanics a greater, net number of risk alleles than Whites ( p < .001). GRS was associated with increased odds of FLD (OR Q5vsQ1 = 8.72 [95% CI = 5.97–13.0], p = 9.8 × 10 −28 ), with the association being stronger in Hispanics (OR Q5vsQ1 = 14.8 [8.3–27.1]) than Blacks (OR Q5vsQ1 = 3.7 [1.5–11.5], P‐interaction = 0.002). After accounting for GRS, the odds of FLD between Hispanics and Whites did not differ significantly (OR = 1.06 [0.87–1.28], p = .58), whereas Blacks retained much lower odds of FLD (OR = 0.21, [0.15–0.30], p < .001). Conclusions Blacks had a lower and Hispanics a greater FLD risk allele burden than Whites. These differences contributed to, but did not fully explain, racial/ethnic differences in FLD prevalence. Identification of additional factors protecting Blacks from FLD may provide new targets for prevention and treatment of FLD.

الإتاحة: https://doi.org/10.1111/liv.15322Test

المؤلفون: Luo, Fei, Smagris, Eriks, Martin, Sarah A., Vale, Goncalo, McDonald, Jeffrey G., Fletcher, Justin A., Burgess, Shawn C., Hobbs, Helen H., Cohen, Jonathan C.

المساهمون: National Institutes of Health, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, China Scholarship Council

المصدر: Cellular and Molecular Gastroenterology and Hepatology ; volume 13, issue 3, page 879-899 ; ISSN 2352-345X

الإتاحة: https://doi.org/10.1016/j.jcmgh.2021.12.008Test
https://api.elsevier.com/content/article/PII:S2352345X21002587?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2352345X21002587?httpAccept=text/plainTest

المؤلفون: BasuRay, Soumik, Wang, Yang, Smagris, Eriks, Cohen, Jonathan C., Hobbs, Helen H.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2019 May 01. 116(19), 9521-9526.

الوصول الحر: https://www.jstor.org/stable/26705139Test

المؤلفون: Banfi, Serena, Gusarova, Viktoria, Gromada, Jesper, Cohen, Jonathan C., Hobbs, Helen H.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2018 Feb 01. 115(6), E1249-E1258.

الوصول الحر: https://www.jstor.org/stable/26507212Test

المؤلفون: Luo, Fei, Xing, Chao, Asrani, Sumeet K., Li, Shili, Liang, Guosheng, Hobbs, Helen H., Cohen, Jonathan C.

المساهمون: National Institutes of Health, Howard Hughes Medical Institute

المصدر: Molecular Metabolism ; volume 53, page 101299 ; ISSN 2212-8778

مصطلحات موضوعية: Cell Biology, Molecular Biology

الإتاحة: https://doi.org/10.1016/j.molmet.2021.101299Test
https://api.elsevier.com/content/article/PII:S2212877821001447?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2212877821001447?httpAccept=text/plainTest