Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2226-2236 |
| Number of pages | 11 |
| Journal | Am. J. Pathol. |
| Volume | 190 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2020 |
Keywords
- leptin
- low density lipoprotein
- proprotein convertase 9
- resistin
- STAT3 protein
- LEP protein, human
- PCSK9 protein, human
- RETN protein, human
- STAT3 protein, human
- adult
- Article
- body mass
- cohort analysis
- controlled study
- enzyme activation
- evaluation study
- female
- gene expression regulation
- gene knockdown
- gene silencing
- Hep-G2 cell line
- human
- human cell
- human tissue
- inflammation
- lipoprotein metabolism
- male
- middle aged
- PCSK9 gene
- priority journal
- promoter region
- protein expression
- protein motif
- protein phosphorylation
- signal transduction
- upregulation
- atherosclerosis
- biosynthesis
- DNA responsive element
- genetics
- metabolism
- obesity
- pathology
- Atherosclerosis
- Gene Expression Regulation, Enzymologic
- Hep G2 Cells
- Humans
- Leptin
- Obesity
- Proprotein Convertase 9
- Resistin
- Response Elements
- STAT3 Transcription Factor
- Up-Regulation
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Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3 : American Journal of Pathology. / Macchi, C.; Greco, M.F.; Botta, M. et al.
In: Am. J. Pathol., Vol. 190, No. 11, 2020, p. 2226-2236.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3
T2 - American Journal of Pathology
AU - Macchi, C.
AU - Greco, M.F.
AU - Botta, M.
AU - Sperandeo, P.
AU - Dongiovanni, P.
AU - Valenti, L.
AU - Cicero, A.F.G.
AU - Borghi, C.
AU - Lupo, M.G.
AU - Romeo, S.
AU - Corsini, A.
AU - Magni, P.
AU - Ferri, N.
AU - Ruscica, M.
N1 - Cited By :2 Export Date: 5 March 2021 CODEN: AJPAA Correspondence Address: Macchi, C.; Dipartimento di Scienze Farmacologiche e Biomolecolari, email: chiara.macchi@unimi.it Chemicals/CAS: proprotein convertase 9; serine protease HTRA1; serine proteinase; LEP protein, human; Leptin; PCSK9 protein, human; Proprotein Convertase 9; Resistin; RETN protein, human; STAT3 protein, human; STAT3 Transcription Factor Funding details: Amgen Funding details: Pfizer Funding details: AstraZeneca Funding details: Sanofi Funding details: Gilead Sciences Funding details: Ionis Pharmaceuticals Funding details: European Commission, EC, 777377 Funding details: Fondazione Cariplo, 2015-0552, 2018-0511 Funding details: Agenzia Italiana del Farmaco, Ministero della Salute, AIFA, RF-2016-02364358 Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca, MIUR Funding details: Novo Nordisk Funding details: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Funding text 1: Supported by Cariplo Foundation grants 2015-0552 and 2018-0511 (M.R.), a MIUR Progetto Eccellenza grant (A.C.), Ricerca Finalizzata Ministero della Salute grant RF-2016-02364358 (L.V.) , a Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico grant (L.V.), and European Union (EU) Programme Horizon 2020 grant agreement 777377 ) for the project LITMUS “Liver Investigation: Testing Marker Utility in Steatohepatitis” (L.V.). Funding text 2: Disclosures: S.R. has been a consultant for, and received lecture fees and research grants from Amgen, Sanofi, and AstraZeneca; A.C. has received honoraria from AstraZeneca, Amgen, Sanofi, Recordati, Novartis, MSD, Mediolanum, DOC, Mylan, and Pfizer; L.V. has been a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept Pharmaceuticals, Diatech Pharmacogenetics, and IONIS. References: Perez-Tilve, D., 'Et tu, leptin?' 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PY - 2020
Y1 - 2020
N2 - In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9. © 2020 American Society for Investigative Pathology
AB - In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9. © 2020 American Society for Investigative Pathology
KW - leptin
KW - low density lipoprotein
KW - proprotein convertase 9
KW - resistin
KW - STAT3 protein
KW - LEP protein, human
KW - PCSK9 protein, human
KW - RETN protein, human
KW - STAT3 protein, human
KW - adult
KW - Article
KW - body mass
KW - cohort analysis
KW - controlled study
KW - enzyme activation
KW - evaluation study
KW - female
KW - gene expression regulation
KW - gene knockdown
KW - gene silencing
KW - Hep-G2 cell line
KW - human
KW - human cell
KW - human tissue
KW - inflammation
KW - lipoprotein metabolism
KW - male
KW - middle aged
KW - PCSK9 gene
KW - priority journal
KW - promoter region
KW - protein expression
KW - protein motif
KW - protein phosphorylation
KW - signal transduction
KW - upregulation
KW - atherosclerosis
KW - biosynthesis
KW - DNA responsive element
KW - genetics
KW - metabolism
KW - obesity
KW - pathology
KW - Atherosclerosis
KW - Gene Expression Regulation, Enzymologic
KW - Hep G2 Cells
KW - Humans
KW - Leptin
KW - Obesity
KW - Proprotein Convertase 9
KW - Resistin
KW - Response Elements
KW - STAT3 Transcription Factor
KW - Up-Regulation
U2 - 10.1016/j.ajpath.2020.07.016
DO - 10.1016/j.ajpath.2020.07.016
M3 - Article
VL - 190
SP - 2226
EP - 2236
JO - Am. J. Pathol.
JF - Am. J. Pathol.
SN - 0002-9440
IS - 11
ER -