Mouse liver injury induces hepatic macrophage FGF23 production

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.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

“…Bone is the primary source of FGF23 under biological homeostasis, however in pathological conditions FGF23 is also produced from multiple non-osseous tissues including heart, thymus, spleen and liver [ 34 , 48 , 49 ]. Hepatic production of FGF23 was previously reported in autosomal dominant polycystic kidney disease, childhood biliary atresia and end-stage liver disease patients [ 32 , 33 , 50 ].…”

“…FGF23 is also produced by non-osseous tissues, including pathological conditions of kidney and liver, e.g. FA-AKI, CCl 4 -ALI, autosomal dominant polycystic kidney disease and childhood biliary atresia [ 24 , 25 , [32] , [33] , [34] , [35] ]. Circulatory FGF23 levels are increased among alcoholics [ 36 , 37 ], however the source, mechanism of regulation and role of FGF23 in ALD remains to be delineated.…”

The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects

“…High levels of serum FGF23 are associated with hypophosphataemia-related rickets ( 91 ), as well as the autosomal dominant hypophosphataemic rickets (ADHR), which is characterized by mutations of two FGF23 cleavage sites Arg179 and Ser180 and is frequently accompanied by markedly elevated serum ALP, which may reflect underlying liver abnormalities ( 92 ). Massive elevations in circulating FGF23 contribute to the elevation of liver inflammation, whereas the normal mouse liver itself possesses very low levels of FGF23 mRNA and protein ( 33 , 93 ). FGF23 could stimulate calcineurin signaling by activating FGF receptor isoform 4 in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines ( 94 ).…”

Approach to Hypophosphatemic Rickets

“…Transient hypophosphatemia after hepatic resection lasts from 1 to several days ( 74-76 ). While previously reported to be independent of FGF23, it is noted that FGF23 gene expression in liver macrophages is stimulated during acute liver injury ( 77 ) and in 2 infants with biliary atresia, FGF23-mediated hypophosphatemia normalized after liver transplantation ( 78 ).…”