FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP‐activated protein kinase–Caspase 6 signal axis

Abstract

Background and Aims NAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver. Approach and Results Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high‐fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+–Ca2+/calmodulin‐dependent protein kinase kinase beta–dependent AMP‐activated protein kinase (AMPK)‐Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. Conclusions Our study identifies FGF4 as a stress‐responsive regulator of liver pathophysiology that acts through an FGFR4‐AMPK‐Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.

Treatment of non-alcoholic steatohepatitis with recombinant Orosomucoid 2, an acute phase protein that attenuates the Erk1/2-PPARγ-Cd36 signaling pathway

“…For liver diseases, many of the pharmacological recombinant protein applications involve hepatokines. For example, as a hepatokine, FGF4 recombinant protein protects liver from NAFLD via the AMP-activated protein kinase-Caspase 6 signaling axis 24 ; The FGF19 and FGF21 administration prevents the pathological progression of 13 NAFLD, including hepatosteatosis and NASH associated with obesity and diabetes 25,26 . In addition, recombinant proteins have also been widely used in other diseases.…”

“…ORM2 in the lysate supernatant was purified with a Ni NTA Beads 6FF gravity column (Smart-Lifesciences, Jiangsu, China). Recombinant mouse ORM2 protein was expressed and purified according to published protocols 24,40 .…”

The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

“…We also determined whether aldometanib could alleviate nonalcoholic steatohepatitis (NASH), which is a progressive form of fatty liver that may develop liver injury and can lead to cirrhosis and hepatocellular carcinoma 46,48,78,79 . We found that twice-daily aldometanib (2 mpk) administration for 1 month significantly alleviated hepatic fibrosis, as determined by Sirius Red staining, and in mice fed with the amylin liver NASH (AMLN) diet for 30 weeks (Fig.…”

Many roads lead to Rome: The FGF4–AMP‐activated protein kinase–Caspase 6 signal axis in NAFLD and NASH

“…The compelling study by Song and colleagues now identifies the so far unnoted family member FGF4 as having hepatoprotective effects through activation of FGF4R and the AMPK–Caspase 6 signaling pathway. [ 3 ] Unlike FGF19 or FGF21 analogues in patients, the preclinical data with rFGF4 showed not only steatosis improvement but remarkably improved inflammation and fibrosis, without apparent metabolic or oncological risks. However, translation from mouse to human clearly requires further studies.…”

“…For instance, Song et al used rFGF4 in NASH mouse models, which raises the question to what extent the applied doses would translate into meaningful effects in patients while preserving a good safety profile. Given the decreased hepatic Fgf4 gene expression in patients with NASH, [ 3 ] stratifying patients into subtypes according to their hepatic Fgf4 expression level could be considered in order to demonstrate a clinical benefit of rFGF4 in humans. Moreover, the hepatic (e.g., tumorigenesis) and extrahepatic (e.g., metabolic, cardiovascular, or possibly oncogenic effects) consequences of rFGF4 in patients with NASH are currently unclear.…”