Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors

Table 1

Regulation of HSCs and development of hepatic fibrosis by various FGF isoforms.

FGF subfamily	Study	Findings
FGF1 subfamily	Lin et al. [16]	FGF2 induces collagen 1α1 and αSMA in HSCs in vitro.; FGF2 increases HSC proliferation mediated by MEK/ERK signaling.
FGF1 subfamily	Nakamura et al. [20]	FGF2 increases proliferation of Lx-2 cells.; Inhibition of FGFR1 does not alter αSMA induction in Lx-2 cells treated with TGFβ.
FGF1 subfamily	Yu et al. [22]	Single and double knockout of FGF1 and FGF2 decreases CCl4 induced hepatic fibrosis.; Single and double FGF1 and FGF2 knockout mice have reduced collagen 1α1 expression but not αSMA.; Desmin expression in the liver remained constant in FGF1 and FGF2 deficient mice indicating FGF1 and FGF2 do not affect HSC proliferation.
FGF1 subfamily	Antoine et al. [13]	FGF2 treatment fails to affect the proliferation of Lx-2 cells or primary rat HSCs in vitro.
FGF1 subfamily	Rosenbaum et al. [23]	TGFβ increases the expression of FGF2 by MFLCs.; FGF2 mediates TGFβ induced HSC proliferation but does not alter expression of fibronectin.
FGF7 subfamily	Steiling et al. [26]	FGF7 is expressed in fibrotic livers but not healthy controls.; FGF7 expression is colocalized with αSMA in stained liver sections.
FGF7 subfamily	Otte et al. [27]	IHC of liver sections from rats treated with phenobarbitone and CCl4 revealed FGF7 is exclusively expressed by HSCs in fibrotic foci.; Severity of hepatic fibrosis correlated positively to FGF7 expression.
FGF7 subfamily	Tsai and Wang [28]	FGF7 accelerates DNA incorporation of BrdU and expression of PCNA in hepatocytes after partial hepatectomy.
FGF9 subfamily	Antoine et al. [13]	FGF9 is expressed in hepatocytes and HSCs basally but is greatly upregulated in HSCs after CCl4 exposure.; FGF16 and FGF20 expression has not been detected in HSCs.; FGF9 induces hepatocyte proliferation but not HSC proliferation.
FGF19 subfamily	Uriarte et al. [15]	FGF15 deficiency reduces hepatic fibrosis in mice treated with DEN and CCl4.; Collagen 1α1, Timp1, αSMA, and CTGF expression induced by CCl4 is mitigated in FGF15 deficient mice.; CCl4 treatment of transgenic mice overexpressing FGF15 have 3-fold higher expression of TGFβ and CTGF compared to WT mice.; FGF15 signaling increases CTGF release from hepatocytes leading to the paracrine activation of HSCs.
FGF19 subfamily	Xu et al. [41]	DMN treated mice cotreated with FGF21 have had reduced fibrosis and mitigated expression of collagen 1α1, αSMA, and TGFβ.; FGF21 reduced TGFβ signaling is observed as a decrease in pSmad2/3 : Smad2/3 ratio.; FGF21 attenuates DMN induced hepatic inflammation and reduces TNFα, IL-6, and IL-1β expression.; In vitro treatment of T6 cells with FGF21 decreases alcohol and PDGF inductions of collagen 1α1, αSMA, and TGFβ.; FGF21 reduces Bcl-2/Bax ratio in vitro in cultured T6 cells.
FGF19 subfamily	Fisher et al. [42]	FGF21 deficient mice fed a MCDD have increased fibrosis with increased expression of collagen 1α1, αSMA, and TGFβ.; MCDD fed FGF21 knockout mice have increased hepatic inflammation with increased expression of MCP-1, MIP1α, IL-1β, and CD36.; The increased expression of profibrotic and proinflammatory genes in FGF21 deficient mice is reversible by continuous subcutaneous infusion of FGF21.