Mouse liver injury induces hepatic macrophage FGF23 production.

Pradeep Kumar,Yunshan Liu,Jacquelyn J Maher,Mark J Czaja,Yang Shen,Francesca Cingolani,Matias A Avila

doi:10.1371/journal.pone.0264743

Pradeep Kumar, Yunshan Liu + Show 5 more

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https://doi.org/10.1371/journal.pone.0264743

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Abstract

Fibroblast growth factor 23 (FGF23) is a bone marrow cell produced hormone that functions in the intestine and kidney to regulate phosphate homeostasis. Increased serum FGF23 is a well-established predictor of mortality in renal disease, but recent findings linking increased levels to hepatic and cardiac diseases have suggested that other organs are sources of FGF23 or targets of its effects. The potential ability of the liver to produce FGF23 in response to hepatocellular injury was therefore examined. Very low levels of Fgf23 mRNA and FGF23 protein were detected in normal mouse liver, but the amounts increased markedly during acute liver injury from the hepatotoxin carbon tetrachloride. Serum levels of intact FGF23 were elevated during liver injury from carbon tetrachloride. Chronic liver injury induced by a high fat diet or elevated bile acids also increased hepatic FGF23 levels. Stimulation of toll-like receptor (TLR) 4-driven inflammation by gut-derived lipopolysaccharide (LPS) underlies many forms of liver injury, and LPS induced Fgf23 in the liver as well as in other organs. The LPS-inducible cytokines IL-1β and TNF increased hepatic Fgf23 expression as did a TLR2 agonist Pam2CSK3. Analysis of Fgf23 expression and FGF23 secretion in different hepatic cell types involved in liver injury identified the resident liver macrophage or Kupffer cell as a source of hepatic FGF23. LPS and cytokines selectively induced the hormone in these cells but not in hepatocytes or hepatic stellate cells. FGF23 failed to exert any autocrine effect on the inflammatory state of Kupffer cells but did trigger proinflammatory activation of hepatocytes. During liver injury inflammatory factors induce Kupffer cell production of FGF23 that may have a paracrine proinflammatory effect on hepatocytes. Liver-produced FGF23 may have systemic hormonal effects as well that influence diseases in in other organs.

Highlights

Fibroblast growth factor 23 (FGF23) is a bone marrow cell produced hormone that regulates phosphate homeostasis through modulation of intestinal absorption and renal excretion
To identify pathophysiological events that trigger hepatic FGF23 expression in the liver, Fgf23 mRNA expression was assessed by Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) during acute mouse hepatic injury from the hepatotoxin CCl4
To determine whether systemic FGF23 levels are affected by hepatic Fgf23 induction during CCl4-induced liver injury, levels of iFGF23 were measured in mouse serum by ELISA

Summary

Introduction

Fibroblast growth factor 23 (FGF23) is a bone marrow cell produced hormone that regulates phosphate homeostasis through modulation of intestinal absorption and renal excretion. Serum FGF23 levels are increased in chronic kidney disease in direct proportion to the loss of renal function. In addition to causing hyperphosphatemia, elevated FGF23 is associated with chronic kidney disease progression and mortality [3,4]. Risk from increased FGF23 is out of proportion to the resultant alterations in bone-mineral metabolism, suggesting that high levels of circulating FGF23 have pathophysiological effects through mechanisms other than the dysregulation of phosphate homeostasis [5]. The primary focus on FGF23’s effects have been in the kidney, elevated FGF23 has been linked to disease outcomes in other organs such as the liver, heart and lung [6–10]. Defining mechanisms of excessive FGF23 production and its pathophysiological effects are of importance to a variety of tissues and the relationship of renal disease to diseases in other organs

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