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Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a hi...

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Autores principales: Li, Zhiqiang, Chiang, Yeun-po, He, Mulin, Worgall, Tilla S., Zhou, Hongwen, Jiang, Xian-Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649732/
https://www.ncbi.nlm.nih.gov/pubmed/34927020
http://dx.doi.org/10.1016/j.isci.2021.103449
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author Li, Zhiqiang
Chiang, Yeun-po
He, Mulin
Worgall, Tilla S.
Zhou, Hongwen
Jiang, Xian-Cheng
author_facet Li, Zhiqiang
Chiang, Yeun-po
He, Mulin
Worgall, Tilla S.
Zhou, Hongwen
Jiang, Xian-Cheng
author_sort Li, Zhiqiang
collection PubMed
description Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis.
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spelling pubmed-86497322021-12-17 Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation Li, Zhiqiang Chiang, Yeun-po He, Mulin Worgall, Tilla S. Zhou, Hongwen Jiang, Xian-Cheng iScience Article Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis. Elsevier 2021-11-15 /pmc/articles/PMC8649732/ /pubmed/34927020 http://dx.doi.org/10.1016/j.isci.2021.103449 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Li, Zhiqiang
Chiang, Yeun-po
He, Mulin
Worgall, Tilla S.
Zhou, Hongwen
Jiang, Xian-Cheng
Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_full Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_fullStr Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_full_unstemmed Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_short Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_sort liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: an effect of glucosylceramide accumulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649732/
https://www.ncbi.nlm.nih.gov/pubmed/34927020
http://dx.doi.org/10.1016/j.isci.2021.103449
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