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Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites...

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Autores principales: Huang, Kuang-Tzu, Chen, Kuang-Den, Hsu, Li-Wen, Kung, Chao-Pin, Li, Shu-Rong, Chen, Chien-Chih, Chiu, King-Wah, Goto, Shigeru, Chen, Chao-Long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019565/
https://www.ncbi.nlm.nih.gov/pubmed/31968655
http://dx.doi.org/10.3390/nu12010270
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author Huang, Kuang-Tzu
Chen, Kuang-Den
Hsu, Li-Wen
Kung, Chao-Pin
Li, Shu-Rong
Chen, Chien-Chih
Chiu, King-Wah
Goto, Shigeru
Chen, Chao-Long
author_facet Huang, Kuang-Tzu
Chen, Kuang-Den
Hsu, Li-Wen
Kung, Chao-Pin
Li, Shu-Rong
Chen, Chien-Chih
Chiu, King-Wah
Goto, Shigeru
Chen, Chao-Long
author_sort Huang, Kuang-Tzu
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.
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spelling pubmed-70195652020-03-09 Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD Huang, Kuang-Tzu Chen, Kuang-Den Hsu, Li-Wen Kung, Chao-Pin Li, Shu-Rong Chen, Chien-Chih Chiu, King-Wah Goto, Shigeru Chen, Chao-Long Nutrients Article Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression. MDPI 2020-01-20 /pmc/articles/PMC7019565/ /pubmed/31968655 http://dx.doi.org/10.3390/nu12010270 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Kuang-Tzu
Chen, Kuang-Den
Hsu, Li-Wen
Kung, Chao-Pin
Li, Shu-Rong
Chen, Chien-Chih
Chiu, King-Wah
Goto, Shigeru
Chen, Chao-Long
Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title_full Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title_fullStr Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title_full_unstemmed Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title_short Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD
title_sort decreased pedf promotes hepatic fatty acid uptake and lipid droplet formation in the pathogenesis of nafld
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019565/
https://www.ncbi.nlm.nih.gov/pubmed/31968655
http://dx.doi.org/10.3390/nu12010270
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