PEDF promotes nuclear degradation of ATGL through COP1

Niyogi, Sougata; Ghosh, Mainak; Adak, Moumita; Chakrabarti, Partha

doi:10.1016/j.bbrc.2019.03.111

Cited by 17 publications

(16 citation statements)

References 23 publications

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“…In the fatty acid mobilization assay, although the total lipid droplet accumulation was increased in PEDF knocked down, lipid-loaded cells, these cells had more diffused red fluorescence, indicating less incorporation into lipid droplets. This observation is consistent with a recent study by Niyogi et al, showing increased fatty acid mobilization in PEDF knocked down HepG2 cells [34]. However, in their study, knocking down PEDF decreased triglyceride accumulation, which is different from our results and a general understanding of PEDF being a lipolytic stimulant.…”

Section: Discussionsupporting

confidence: 88%

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: Discussionsupporting

confidence: 88%

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

et al. 2020

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“…The ATGL lipase supports HCV production associated, and a nuclear protein pool. The shuttling of ATGL for degradation in the nucleus was previously reported [51] but to our knowledge, the mechanism supporting ABHD5 translocation to the nucleus is unknown. The possible nuclear function of these two proteins would be worth investigating, especially in light of the blooming literature on nuclear lipid droplets (see for instance [52,53]).…”

Section: Plos Pathogensmentioning

confidence: 78%

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

et al. 2020

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Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.

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“…Interestingly, ATGL is the specific receptor of pigment epithelium-derived factor (PEDF), which is a tumor suppressor gene [72,73]. A connection between tumor invasion, PEDF depletion, and lipid accumulation has been established in the pancreas [74] and PEDF also functions as tumor suppressor gene in the process of epithelialmesenchymal transition and metastasis in NPC [75].…”

Section: Discussionmentioning

confidence: 99%

“…A connection between tumor invasion, PEDF depletion, and lipid accumulation has been established in the pancreas [74] and PEDF also functions as tumor suppressor gene in the process of epithelialmesenchymal transition and metastasis in NPC [75]. While several studies have shown that PEDF regulates triglycerol dependent on ATGL polyubiquitination [73,76], so ATGL might function as a hub regulating the lipid metabolism and tumor development.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of adipose triglyceride lipase by EB viral‐encoded LMP2A links lipid accumulation to increased migration in nasopharyngeal carcinoma

et al. 2020

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NNE normal nasopharyngeal epithelium EIF4E eukaryotic translation initiation factor 4E gene LC-MC liquid chromatography-mass spectrometry PLS-DA partial least squares-discriminant analysis OCR oxygen consumption rate ECAR extracellular acidification rate FCCP carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone IHC Immunohistochemistry siRNA small interfering RNA ROS reactive oxygen species PEDF pigment epithelium-derived factor

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PEDF promotes nuclear degradation of ATGL through COP1

Cited by 17 publications

References 23 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

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

Downregulation of adipose triglyceride lipase by EB viral‐encoded LMP2A links lipid accumulation to increased migration in nasopharyngeal carcinoma

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