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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Bibliographic Details
Published in:Nutrients 2020-01, Vol.12 (1), p.270
Main Authors: 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
Format: Article
Language:English
Subjects:
Accumulation
adipose triglyceride lipase
Antigens
cd36
CD36 antigen
Cell culture
Cirrhosis
Diabetes
Droplets
Epithelium
Fatty acid-binding protein
Fatty acids
Fatty liver
Fibrosis
Gene expression
Hepatocytes
Lipase
lipid droplets
Lipids
Lipolysis
Liver
Liver cirrhosis
Liver diseases
Metabolism
Metabolites
Obesity
Pigment epithelium-derived factor
Protein transport
Proteins
Sequence analysis
Steatosis
Triglycerides
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Summary: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.
ISSN:2072-6643
2072-6643
DOI:10.3390/nu12010270