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
Marlies Schippers,
Eduard Post,
Ilse Eichhorn,
Jitske Langeland,
Leonie Beljaars,
Madhu S. Malo,
Richard A. Hodin,
José Luis Millán,
Yury Popov,
Detlef Schuppan,
Klaas Poelstra
Affiliations
Marlies Schippers
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Eduard Post
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Ilse Eichhorn
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Jitske Langeland
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Leonie Beljaars
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Madhu S. Malo
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Richard A. Hodin
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
José Luis Millán
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Yury Popov
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Detlef Schuppan
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Klaas Poelstra
Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
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.
