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

Publisher: MDPI Publishing Country of Publication: Switzerland NLM ID: 101521595 Publication Model: Electronic Cited Medium: Internet ISSN: 2072-6643 (Electronic) Linking ISSN: 20726643 NLM ISO Abbreviation: Nutrients Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI Publishing

Eye Proteins/*metabolism ; Fatty Acids/*metabolism ; Hepatocytes/*metabolism ; Lipid Droplets/*metabolism ; Liver/*metabolism ; Nerve Growth Factors/*metabolism ; Non-alcoholic Fatty Liver Disease/*metabolism ; Serpins/*metabolism; Animals ; CD36 Antigens/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Down-Regulation ; Eye Proteins/genetics ; Fatty Acid-Binding Proteins/metabolism ; Hepatocytes/pathology ; Humans ; Liver/pathology ; Male ; Mice, Inbred C57BL ; Nerve Growth Factors/genetics ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/pathology ; Serpins/genetics

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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MOST 108-2320-B-182A-006 Ministry of Science and Technology, Taiwan; MOST 107-2320-B-182A-027 Ministry of Science and Technology, Taiwan; CMRPG8G1381 Chang Gung Medical Foundation

Keywords: CD36; adipose triglyceride lipase; fatty acids; lipid droplets; pigment epithelium-derived factor

0 (CD36 Antigens)
0 (Cd36 protein, mouse)
0 (Eye Proteins)
0 (Fabp1 protein, mouse)
0 (Fatty Acid-Binding Proteins)
0 (Fatty Acids)
0 (Nerve Growth Factors)
0 (Serpins)
0 (pigment epithelium-derived factor)

Date Created: 20200124 Date Completed: 20201116 Latest Revision: 20201116

20221213

PMC7019565

10.3390/nu12010270

31968655