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Open AccessArticle

Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis

1
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
2
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
3
Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka 1000, Bangladesh
4
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
5
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
6
Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(12), 2708; https://doi.org/10.3390/cells9122708
Received: 30 September 2020 / Revised: 11 December 2020 / Accepted: 14 December 2020 / Published: 17 December 2020
Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin+− and αSMA+ −HSC and CD68+− macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis. View Full-Text
Keywords: lipopolysaccharide; lipid A; hepatic stellate cells; liver fibrosis; alkaline phosphatase lipopolysaccharide; lipid A; hepatic stellate cells; liver fibrosis; alkaline phosphatase
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MDPI and ACS Style

Schippers, M.; Post, E.; Eichhorn, I.; Langeland, J.; Beljaars, L.; Malo, M.S.; Hodin, R.A.; Millán, J.L.; Popov, Y.; Schuppan, D.; Poelstra, K. Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis. Cells 2020, 9, 2708. https://doi.org/10.3390/cells9122708

AMA Style

Schippers M, Post E, Eichhorn I, Langeland J, Beljaars L, Malo MS, Hodin RA, Millán JL, Popov Y, Schuppan D, Poelstra K. Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis. Cells. 2020; 9(12):2708. https://doi.org/10.3390/cells9122708

Chicago/Turabian Style

Schippers, Marlies; Post, Eduard; Eichhorn, Ilse; Langeland, Jitske; Beljaars, Leonie; Malo, Madhu S.; Hodin, Richard A.; Millán, José L.; Popov, Yury; Schuppan, Detlef; Poelstra, Klaas. 2020. "Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis" Cells 9, no. 12: 2708. https://doi.org/10.3390/cells9122708

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