Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice

Yoshida, Takafumi; Akiba, Jun; Matsui, Takanori; Nakamura, Kazuo; Hisamoto, Takao; Abe, Mitsuhiko; Ikezono, Yu; Wada, Fumitaka; Iwamoto, Hideki; Nakamura, Tõru; Koga, Hironori; Yamagishi, Sho‐ichi; Torimura, Takuji

doi:10.1007/s10620-017-4550-x

Cited by 21 publications

(17 citation statements)

References 33 publications

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“…However, the function of PEDF in the liver remains largely unknown. Studies have shown that PEDF has anti-oxidative capacities and protects hepatocytes from inflammation-induced cell death during NASH progression [14,16], suggesting that PEDF is an important hepatokine beyond merely being a lipolytic agent. In this study, we demonstrate that decreased PEDF expression, observed in the mouse fatty liver, enhances fatty acid uptake and resultant lipid accumulation and mobilization in vitro, with a concomitant increase in fatty acid transport proteins CD36 and FABP1, but not FATP2 and FATP4.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 99%

“…Despite its pathogenic potential, PEDF seems to play a protective role in the liver. PEDF reduces high fat diet induced obesity and NAFLD progression through its antioxidant and anti-inflammatory capacity in several animal studies [14][15][16]. However, how PEDF regulates hepatic lipid accumulation remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…PEDF has been suggested to be a potential therapeutic agent in NASH and liver fibrosis putatively by directly inhibiting hepatic stellate cell activation or by upregulating matrix metalloproteinase 2 (19,20). In addition, knockout of PEDF or gene transfer to the liver also demonstrated its role in steatosis (21,42), although the precise molecular events underlying those results remain obscure. However, the role of PEDF in preventing hepatocyte ballooning or death, the pathognomonic hallmark that differentiates NASH from simple steatosis, has not yet been addressed.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium‐derived factor expression

et al. 2018

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Hepatocellular death or ballooning distinguishes the transition of simple steatosis to irreversible nonalcoholic steatohepatitis (NASH). However, the molecular mechanism of hepatocellular apoptosis in NASH is largely unclear, and discovery of endogenous mediators that could prevent or inhibit cell death is thereby critical in intercepting NASH progression. Here, we identified pigment epithelium-derived factor (PEDF), a secreted, moonlighting hepatokine as 1 hepatoprotective agent in mice with diet-induced NASH. Hepatic PEDF expression is induced by IL-1β, which is derived from inflammasome activation in liver-resident Kupffer cells, an effect that is negatively regulated by TNF-α and predominantly secreted by monocyte-derived, recruited, hepatic macrophages. Mechanistically, reciprocal and opposing roles for IL-1β and TNF-α in PEDF expression are mediated by differential activation of NF-κB. Although augmented TNF-α production leads to temporal reduction of PEDF expression in NASH, PEDF conversely abrogates TNF-α-mediated hepatocyte death by modulating the extrinsic apoptosis pathway. Thus, our study highlights PEDF as a functionally important hepatokine in NASH progression by linking inflammasome activation and hepatocellular death.-Adak, M., Das, D., Niyogi, S., Nagalakshmi, C., Ray, D., Chakrabarti, P. Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium-derived factor expression.

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“…SOD1 induces Rac1 activity that in turn mediates NOX1 and then NOX4 activation . Rac1 is also involved in hepatic inflammation, and it is an important corollary for NOX2 activation …”

Section: Hscs Nox and Liver Fibrosismentioning

confidence: 99%

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: A review

Mortezaee

2018

Cell Biochemistry & Function

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Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice

Cited by 21 publications

References 33 publications

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

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

Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium‐derived factor expression

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: A review

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