Abstract:
Neurological dysfunction, one of the consequences of acute liver failure (ALF), and also referred to as hepatic
encephalopathy (HE), contributes to mortality posing challenges for clinical management. FGF21 has been
implicated in the inhibition of cognitive decline and fibrogenesis. However, the effects of FGF21 on the clinical
and molecular presentations of HE has not been elucidated. HE was induced by fulminant hepatic failure using
thioacetamide (TAA) in male C57BL/6J mice while controls were injected with saline. For two consecutive weeks,
mice were treated intraperitoneally with FGF21 (3 mg/kg) while controls were treated with saline. Cognitive, neu-
rological, and activity function scores were recorded. Serum, liver, and brain samples were taken for analysis of
CCL5 and GABA by ELISA, and RT qPCR was used to measure the expressions of fibrotic and pro-inflammatory
markers. We report significant improvement in both cognitive and neurological scores by FGF21 treatment after
impairment by TAA. GABA and CCL5, key factors in the progression of HE were also significantly reduced in
the treatment group. Furthermore, the expression of fibrotic markers such as TGFβ and Col1 were also
significantly downregulated after FGF21 treatment. TNFα and IL-6 were significantly reduced in the liver while
in the brain, TNFα and IL-1 were downregulated. However, both in the liver and the brain, IL-10 was significantly
upregulated. FGF21 inhibits CXCR4/CCL5 activation and upregulates the production of IL-10 in the damaged
liver stimulating the production pro-inflammatory cytokines and apoptosis of hepatic stellate cells through the
STAT3-SOCS3 pathway terminating the underlying fibrosis in HE.
