Lipid-Independent Regulation of PLIN5 via IL-6 through the JAK/STAT3 Axis in Hep3B Cells

Perilipin 5 (PLIN5) is a lipid droplet coat protein that is highly expressed in oxidative tissues such as those of muscles, the heart and the liver. PLIN5 expression is regulated by a family of peroxisome proliferator-activated receptors (PPARs) and modulated by the cellular lipid status. So far, research has focused on the role of PLIN5 in the context of non-alcoholic fatty liver disease (NAFLD) and specifically in lipid droplet formation and lipolysis, where PLIN5 serves as a regulator of lipid metabolism. In addition, there are only limited studies connecting PLIN5 to hepatocellular carcinoma (HCC), where PLIN5 expression is proven to be upregulated in hepatic tissue. Considering that HCC development is highly driven by cytokines present throughout NAFLD development and in the tumor microenvironment, we here explore the possible regulation of PLIN5 by cytokines known to be involved in HCC and NAFLD progression. We demonstrate that PLIN5 expression is strongly induced by interleukin-6 (IL-6) in a dose- and time-dependent manner in Hep3B cells. Moreover, IL-6-dependent PLIN5 upregulation is mediated by the JAK/STAT3 signaling pathway, which can be blocked by transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α). Furthermore, IL-6-mediated PLIN5 upregulation changes when IL-6 trans-signaling is stimulated through the addition of soluble IL-6R. In sum, this study sheds light on lipid-independent regulation of PLIN5 expression in the liver, making PLIN5 a crucial target for NAFLD-induced HCC.

[1]  K. Magalhães,et al.  Inflammasome-Mediated Cytokines: A Key Connection between Obesity-Associated NASH and Liver Cancer Progression , 2022, Biomedicines.

[2]  P. Sehgal.  Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells , 2022, Cells.

[3]  D. Lieberman,et al.  Interleukin 6 as an energy allocator in muscle tissue , 2022, Nature Metabolism.

[4]  R. Weiskirchen,et al.  Lipocalin-2 (LCN2) Deficiency Leads to Cellular Changes in Highly Metastatic Human Prostate Cancer Cell Line PC-3 , 2022, Cells.

[5]  Mingyue Zhu,et al.  IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma , 2021, Frontiers in Oncology.

[6]  J. O’Beirne,et al.  Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach , 2021, Cancers.

[7]  Qian Sun,et al.  Leptin Reduces Plin5 m6A Methylation through FTO to Regulate Lipolysis in Piglets , 2021, International journal of molecular sciences.

[8]  A. Boonstra,et al.  The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma , 2021, Cancers.

[9]  R. Weiskirchen,et al.  Perilipin 5 Ameliorates Hepatic Stellate Cell Activation via SMAD2/3 and SNAIL Signaling Pathways and Suppresses STAT3 Activation , 2021, Cells.

[10]  R. Weiskirchen,et al.  Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights , 2021, International journal of molecular sciences.

[11]  Liyi Xie,et al.  Perilipin 5 ameliorates high-glucose-induced podocyte injury via Akt/GSK-3β/Nrf2-mediated suppression of apoptosis, oxidative stress, and inflammation. , 2021, Biochemical and biophysical research communications.

[12]  G. Zibari,et al.  Addressing the worldwide hepatocellular carcinoma: epidemiology, prevention and management. , 2020, Journal of gastrointestinal oncology.

[13]  Akshatha N. Srinivas,et al.  Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease , 2020, Frontiers in Oncology.

[14]  Runzhi Huang,et al.  Identification of prognostic and metastasis-related alternative splicing signatures in hepatocellular carcinoma , 2020, Bioscience reports.

[15]  B. Sitek,et al.  Deletion of Perilipin 5 Protects against Hepatic Injury in Nonalcoholic Fatty Liver Disease via Missing Inflammasome Activation , 2020, Cells.

[16]  Hongbo Hu,et al.  Involvement of activation of PLIN5-Sirt1 axis in protective effect of glycycoumarin on hepatic lipotoxicity. , 2020, Biochemical and biophysical research communications.

[17]  Xing Gao,et al.  Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[18]  D. Fan,et al.  Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP , 2020, Theranostics.

[19]  Liqing Yu,et al.  CGI-58: Versatile Regulator of Intracellular Lipid Droplet Homeostasis. , 2020, Advances in experimental medicine and biology.

[20]  T. Petan,et al.  Lipid Droplets and the Management of Cellular Stress , 2019, The Yale journal of biology and medicine.

[21]  M. Koenders,et al.  TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression. , 2019, Osteoarthritis and cartilage.

[22]  J. Gingold,et al.  Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma. , 2019, Trends in molecular medicine.

[23]  Jianqiu Gu,et al.  Oleic acid-induced perilipin 5 expression and lipid droplets formation are regulated by the PI3K/PPARα pathway in HepG2 cells. , 2019, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[24]  R. Findeisen,et al.  Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling , 2019, Cell Communication and Signaling.

[25]  T. Luedde,et al.  Perilipin 5 and Lipocalin 2 Expression in Hepatocellular Carcinoma , 2019, Cancers.

[26]  Yajin Chen,et al.  TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma , 2018, EBioMedicine.

[27]  E. Shakiba,et al.  Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis , 2018, Clinical and experimental hepatology.

[28]  Long Yan,et al.  Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma , 2018, Journal of experimental & clinical cancer research : CR.

[29]  H. Pilegaard,et al.  Impact of skeletal muscle IL-6 on regulation of liver and adipose tissue metabolism during fasting , 2018, Pflügers Archiv - European Journal of Physiology.

[30]  J. Scheller,et al.  The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling , 2018, The Journal of Biological Chemistry.

[31]  S. Zheng,et al.  Hall of Fame among Pro-inflammatory Cytokines: Interleukin-6 Gene and Its Transcriptional Regulation Mechanisms , 2016, Front. Immunol..

[32]  H. Guillou,et al.  Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle , 2016, Scientific Reports.

[33]  P. Bickel,et al.  Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function , 2016, Nature Communications.

[34]  L. Gan,et al.  SOCS3 promotes inflammation and apoptosis via inhibiting JAK2/STAT3 signaling pathway in 3T3-L1 adipocyte. , 2015, Immunobiology.

[35]  S. Rose-John,et al.  The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. , 2015, Current opinion in immunology.

[36]  S. Rose-John,et al.  Interleukin-6 and its receptors: a highly regulated and dynamic system. , 2014, Cytokine.

[37]  K. Cheng,et al.  Rather than interleukin‐27, interleukin‐6 expresses positive correlation with liver severity in naïve hepatitis B infection patients , 2012, Liver international : official journal of the International Association for the Study of the Liver.

[38]  H. Robenek,et al.  Lipid droplet associated proteins: an emerging role in atherogenesis. , 2011, Histology and histopathology.

[39]  R. Weiskirchen,et al.  Induction of lipocalin‐2 expression in acute and chronic experimental liver injury moderated by pro‐inflammatory cytokines interleukin‐1β through nuclear factor‐κB activation , 2011, Liver international : official journal of the International Association for the Study of the Liver.

[40]  R. Weiskirchen,et al.  Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling. , 2011, Cellular signalling.

[41]  M. Zvelebil,et al.  Exploring the specificity of the PI3K family inhibitor LY294002. , 2007, The Biochemical journal.

[42]  C. Sztalryd,et al.  LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues. , 2007, Biochimica et biophysica acta.

[43]  N. Wolins,et al.  OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization , 2006, Diabetes.

[44]  Bianca Sperl,et al.  Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. , 2006, Chemistry & biology.

[45]  T. Osumi,et al.  MLDP, a Novel PAT Family Protein Localized to Lipid Droplets and Enriched in the Heart, Is Regulated by Peroxisome Proliferator-activated Receptor α* , 2006, Journal of Biological Chemistry.

[46]  A. Gressner,et al.  N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug. , 2005, Biochemical pharmacology.

[47]  S. Schneider,et al.  0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(11):5577–5582 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0603 Interleukin-6 Regulates Human Adipose Tissue Lipid Metabolism and Leptin Produc , 2022 .

[48]  B. Saltin,et al.  Interleukin-6 stimulates lipolysis and fat oxidation in humans. , 2003, The Journal of clinical endocrinology and metabolism.

[49]  M. Neurath,et al.  Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. , 2001, European journal of biochemistry.

[50]  T. Taga.  IL6 signalling through IL6 receptor and receptor-associated signal transducer, gp130. , 1992, Research in immunology.

[51]  T. Yamane,et al.  Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. , 1982, Cancer research.

[52]  Ivan Damjanov,et al.  Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line , 1979, Nature.