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Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) can advance, if untreated, to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure and liver-related death. In the United States, NASH affects approximately 2–5% of the population an...

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Autores principales: Oniciu, Daniela Carmen, Hashiguchi, Taishi, Shibazaki, Yuichiro, Bisgaier, Charles L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976190/
https://www.ncbi.nlm.nih.gov/pubmed/29847555
http://dx.doi.org/10.1371/journal.pone.0194568
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author Oniciu, Daniela Carmen
Hashiguchi, Taishi
Shibazaki, Yuichiro
Bisgaier, Charles L.
author_facet Oniciu, Daniela Carmen
Hashiguchi, Taishi
Shibazaki, Yuichiro
Bisgaier, Charles L.
author_sort Oniciu, Daniela Carmen
collection PubMed
description BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) can advance, if untreated, to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure and liver-related death. In the United States, NASH affects approximately 2–5% of the population and an additional 10–30% have NAFLD. The number of drugs in development for NASH is growing steadily, along with nonclinical models to support prediction of clinical success. Here we evaluate gemcabene, a first-in-class clinical candidate for dyslipidemia, for its potential utility, based on its combined lipid-lowering and anti-inflammatory efficacy in clinical trials, in a preclinical model of NASH. METHODS: Gemcabene was evaluated in the STAM™ murine model of NASH. Gemcabene intervention in mice made diabetic with streptozotocin and fed a high fat high-caloric diet was assessed for changes in plasma, and hepatic histological and mRNA markers of lipid metabolism and inflammation. RESULTS: Gemcabene significantly downregulated hepatic mRNA markers of inflammation (TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB), lipogenesis and lipid modulation (ApoC-III, ACC1, ADH-4, Sulf-2), and fibrosis (TIMP-1 and MMP-2). These effects are important for the prevention of steatosis, inflammation, and hepatocyte ballooning (i.e., the components of the NAFLD Activity Score or NAS), and inhibition of fibrosis progression, and were observed following treatment with gemcabene. CONCLUSIONS: These non-clinical findings corroborate with existing clinical data to support the clinical evaluation of gemcabene as a potential new treatment for NASH.
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spelling pubmed-59761902018-06-17 Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH Oniciu, Daniela Carmen Hashiguchi, Taishi Shibazaki, Yuichiro Bisgaier, Charles L. PLoS One Research Article BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) can advance, if untreated, to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure and liver-related death. In the United States, NASH affects approximately 2–5% of the population and an additional 10–30% have NAFLD. The number of drugs in development for NASH is growing steadily, along with nonclinical models to support prediction of clinical success. Here we evaluate gemcabene, a first-in-class clinical candidate for dyslipidemia, for its potential utility, based on its combined lipid-lowering and anti-inflammatory efficacy in clinical trials, in a preclinical model of NASH. METHODS: Gemcabene was evaluated in the STAM™ murine model of NASH. Gemcabene intervention in mice made diabetic with streptozotocin and fed a high fat high-caloric diet was assessed for changes in plasma, and hepatic histological and mRNA markers of lipid metabolism and inflammation. RESULTS: Gemcabene significantly downregulated hepatic mRNA markers of inflammation (TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB), lipogenesis and lipid modulation (ApoC-III, ACC1, ADH-4, Sulf-2), and fibrosis (TIMP-1 and MMP-2). These effects are important for the prevention of steatosis, inflammation, and hepatocyte ballooning (i.e., the components of the NAFLD Activity Score or NAS), and inhibition of fibrosis progression, and were observed following treatment with gemcabene. CONCLUSIONS: These non-clinical findings corroborate with existing clinical data to support the clinical evaluation of gemcabene as a potential new treatment for NASH. Public Library of Science 2018-05-30 /pmc/articles/PMC5976190/ /pubmed/29847555 http://dx.doi.org/10.1371/journal.pone.0194568 Text en © 2018 Oniciu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Oniciu, Daniela Carmen
Hashiguchi, Taishi
Shibazaki, Yuichiro
Bisgaier, Charles L.
Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title_full Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title_fullStr Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title_full_unstemmed Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title_short Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH
title_sort gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the stam™ model of nash
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976190/
https://www.ncbi.nlm.nih.gov/pubmed/29847555
http://dx.doi.org/10.1371/journal.pone.0194568
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