Fibroblast Growth Factor-5 Participates in the Progression of Hepatic Fibrosis

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation, and fibrosis and is believed to develop via a “two-hit process”; however, its pathophysiology remains unclear. Fibroblast growth factors (FGFs) are heparin-binding polypeptides with diverse biological activities in many developmental and metabolic processes. In particular, FGF5 is associated with high blood pressure. We investigated the function of FGF5 in vivo using spontaneously Fgf5 null mice and explored the role of diet in the development of NASH. Mice fed a high-fat diet gained little weight and had higher serum alanine transaminase, aspartate amino transferase, and non–high-density lipoprotein-cholesterol levels. Liver histology indicated marked inflammation, focal necrosis, fat deposition, and fibrosis, similar to the characteristics of NASH. FGF5 and a high-fat diet play significant roles in the pathophysiology of hepatic fibrosis and Fgf5 null mice may provide a suitable model for liver fibrosis or NASH.

Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice

“…Severe hepatic injury was observed in LH mice fed the HFD (LH HFD) for 8 weeks but not in LH mice fed control diet (LH CD) as previously reported ( Fig. 1A ) 21 . Also, WT mice fed the HFD (WT HFD) had higher serum alanine amino transferase (ALT) levels than WT mice fed the CD (WT CD) ( Fig.…”

“…FGF5 is known to be a molecule that determines the length of body hair of mammals 17 18 19 including humans 20 , and mice deficient in this gene have long hair (LH) compared to wild type (WT) mice 21 . Recently, some studies have reported that the single nucleotide mutation (polymorphism) of this gene is associated with hypertension in humans 22 23 24 25 .…”

“…Recently, some studies have reported that the single nucleotide mutation (polymorphism) of this gene is associated with hypertension in humans 22 23 24 25 . We have reported that a high fat diet (HFD) increased non-HDL cholesterol levels in FGF5 null LH mice and induced steatohepatitis resembling human NASH 21 . In the present study, based on our recent subclassification of Kupffer cell phenotypes, we investigated the immunological mechanism of this experimental model of NASH.…”

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

“…However, other studies demonstrated no vitamin D-independent functions of FGF23 in glucose homeostasis, insulin signaling or fat metabolism in mice (Streicher et al, 2012). Finally, the paracrine FGF5 and FGF10 have been shown to regulate lipid accumulation in liver, and adipogenesis in fat, respectively (Sakaue et al, 2002;Asaki et al, 2004;Hanaka et al, 2014). Further studies are needed to evaluate the role of the other FGFs in metabolism and their underlying mechanisms of action.…”

“…FGF1 acts on FGFR1 in the brain to suppress food intake (Suh et al, 2014;Scarlett et al, 2016). FGF5 acts on FGFR1 to suppress lipid accumulation in the liver (Hanaka et al, 2014). FGF10 acts on FGFR2 to increase adipogenesis in adipocytes (Sakaue et al, 2002;Asaki et al, 2004).…”