Mfap4: a promising target for enhanced liver regeneration and chronic liver disease treatment

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Abstract

The liver has a remarkable regenerative capacity. Nevertheless, under chronic liver-damaging conditions, this capacity becomes exhausted, allowing the accumulation of fibrotic tissue and leading to end-stage liver disease. Enhancing the endogenous regenerative capacity by targeting regeneration breaks is an innovative therapeutic approach. We set up an in vivo functional genetic screen to identify such regeneration breaks. As the top hit, we identified Microfibril associated protein 4 (Mfap4). Knockdown of Mfap4 in hepatocytes enhances cell proliferation, accelerates liver regeneration, and attenuates chronic liver disease by reducing liver fibrosis. Targeting Mfap4 modulates several liver regeneration-related pathways including mTOR. Our research opens the way to siRNA-based therapeutics to enhance hepatocyte-based liver regeneration.

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Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

Maxim Kuleshov, Matthew Jones, Andrew D. Rouillard … (2016)

Enrichment analysis is a popular method for analyzing gene sets generated by genome-wide experiments. Here we present a significant update to one of the tools in this domain called Enrichr. Enrichr currently contains a large collection of diverse gene set libraries available for analysis and download. In total, Enrichr currently contains 180 184 annotated gene sets from 102 gene set libraries. New features have been added to Enrichr including the ability to submit fuzzy sets, upload BED files, improved application programming interface and visualization of the results as clustergrams. Overall, Enrichr is a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries. Enrichr is freely available at: http://amp.pharm.mssm.edu/Enrichr.

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Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

Edward Chen, Christopher M Tan, Yan Kou … (2013)

Background System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Results Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Conclusions Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr.

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Burden of liver diseases in the world

Sumeet K Asrani, Harshad Devarbhavi, John Eaton … (2019)

Liver disease accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma. Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. Though these numbers are sobering, they highlight an important opportunity to improve public health given that most causes of liver diseases are preventable.

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Author and article information

Contributors

Torsten Wuestefeld: wustefeldt@gis.a-star.edu.sg

Journal

Journal ID (nlm-ta): NPJ Regen Med

Journal ID (iso-abbrev): NPJ Regen Med

Title: NPJ Regenerative Medicine

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2057-3995

Publication date (Electronic): 7 November 2023

Publication date PMC-release: 7 November 2023

Publication date Collection: 2023

Volume: 8

Electronic Location Identifier: 63

Affiliations

[1 ]Laboratory of In Vivo Genetics and Gene Therapy, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), ( https://ror.org/05k8wg936) 60 Biopolis Street, Singapore, 138672 Republic of Singapore

[2 ]Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 119228 Republic of Singapore

[3 ]Laboratory of Translational Cancer Biology, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), ( https://ror.org/05k8wg936) 60 Biopolis Street, Singapore, 138672 Republic of Singapore

[4 ]GRID grid.458458.0, ISNI 0000 0004 1792 6416, Key Laboratory of Zoological Systematics and Evolution, , Institute of Zoology, Chinese Academy of Sciences, ; 100101 Beijing, China

[5 ]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, ( https://ror.org/034t30j35) Kunming, 650223 China

[6 ]Cancer Science Institute of Singapore, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117599 Republic of Singapore

[7 ]Division of Gastroenterology and Hepatology, National University Health System, ( https://ror.org/05tjjsh18) Singapore, 119074 Republic of Singapore

[8 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, School of Biological Science, , Nanyang University of Singapore, ; Singapore, 637551 Republic of Singapore

[9 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, National Cancer Centre, ; Singapore, 169610 Republic of Singapore

[10 ]Present Address: Cancer Science Institute of Singapore, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117599 Republic of Singapore

Author information

May Yin Lee http://orcid.org/0000-0003-2366-9463

Wai Leong Tam http://orcid.org/0000-0003-2365-5264

Article

Publisher ID: 337

DOI: 10.1038/s41536-023-00337-9

PMC ID: 10630300

PubMed ID: 37935709

SO-VID: c81f00f4-9227-4c89-9428-9ec0098131d0

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 27 March 2023

Date accepted : 11 October 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001349, MOH | National Medical Research Council (NMRC);

Award ID: NMRC/OFIRG/0063/2017

Award Recipient : Torsten Wuestefeld

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Keywords: rnai,non-alcoholic fatty liver disease,liver fibrosis

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Keywords: rnai, non-alcoholic fatty liver disease, liver fibrosis

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Mfap4: a promising target for enhanced liver regeneration and chronic liver disease treatment

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Most cited references 64

Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

Burden of liver diseases in the world

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