Abstract
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.
Highlights
One of the serum factors that changes profoundly during hepatic fibrosis, as well as in many other liver diseases, is serum alkaline phosphatase (AP) activity
We examined the effects of wild-type LPS, di-phosphoryl lipid A, and mono-phosphoryl lipid A on mouse RAW264.7 macrophages (ECACC, Porton Down, Wiltshire, UK) and in cultures of primary rat hepatic stellate cells, isolated from normal rat livers. rHSC (200,000 cells/mL) or RAW cells (100,000 cells/mL) were incubated for 24 h with wild-type LPS from E. coli (100 ng/mL) or DPLA (100 ng/mL) or Mono-phosphoryl lipid A (MPLA) (100 ng/mL), both from
The present study shows that LPS, in particular the lipid A moiety thereof, significantly affects macrophage and fibroblast activities, and the fibrogenic process within the fibrotic liver
Summary
One of the serum factors that changes profoundly during hepatic fibrosis, as well as in many other liver diseases, is serum alkaline phosphatase (AP) activity. Most biological effects of LPS are due to the presence of the lipid A moiety [3], which is a fairly conserved part of this otherwise highly variable molecule among Gram-negative bacterial species. Phosphate groups in this lipid A region critically determine the biological effects of LPS [3]; they affect the binding of LPS to TLR4 and subsequent NFkB activation [4], and the host response towards LPS molecules [5,6] and even mediate resistance to antimicrobial peptides [7].
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