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iNature non-alcoholic fatty liver disease (NAFLD) represents a growing health problem associated with obesity and diabetes for which there is no effective medical treatment
.
There is increasing evidence that several fibroblast growth factors (FGFs) play important roles in different aspects of liver pathophysiology
.
On February 12, 2022, Wenzhou Medical University Huang Zhifeng, Li Xiaokun and Chen Yongping (Song Lintao, Wang Luyao and Hou Yushu are the co-first authors) published a joint communication online in Hepatology (IF=17) entitled "FGF4 protects the liver from non -alcoholic fatty liver disease by activating the AMPK-Caspase 6 signal axis", which reports a previously unappreciated role of FGF4 in the liver
.
In human patients and mouse models, hepatic FGF4 expression was inversely correlated with NAFLD pathological grade
.
Loss of hepatic Fgf4 exacerbates hepatic steatosis and liver injury induced by an obese high-fat diet (HFD)
.
In contrast, exogenous recombinant rFGF4 was found to significantly reduce liver steatosis, inflammation, liver injury and fibrosis in NAFLD/NASH mice, thereby improving or even reversing NAFLD/NASH
.
These beneficial effects of FGF4 are mainly mediated by activation of hepatic FGFR4, which activates the downstream Ca2+-CaMKKβ-dependent AMPK-Caspase 6 signaling axis, resulting in enhanced fatty acid oxidation, reduced hepatocyte apoptosis, and reduced liver injury
.
In conclusion, this study identifies FGF4 as a novel stress response regulator of liver pathophysiology that acts through the FGFR4-AMPK-Caspase 6 signaling pathway, revealing novel strategies for the treatment of NAFLD and related liver lesions
.
Nonalcoholic fatty liver disease (NAFLD), defined as excessive lipid accumulation in the absence of chronic alcohol intake, is considered a hepatic manifestation of metabolic syndrome and can manifest as a spectrum of liver lesions ranging from simple steatosis (non-alcoholic steatosis).
Alcoholic fatty liver, NAFL), non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis to hepatocellular carcinoma (HCC)
.
NAFLD is fast becoming one of the most worrisome public health problems globally due to the increasing prevalence of obesity and diabetes
.
NASH is typically characterized by the presence of NAFL, lobular inflammation, and hepatocyte ballooning, which are important risk factors for fibrosis, which can further develop into cirrhosis and HCC
.
Despite widespread occurrence and a high risk of more severe disease, NAFLD and NASH remain without an approved drug treatment to date, creating an urgent medical need
.
The pathogenesis of NAFLD and NASH is multifactorial, with hepatic lipid accumulation and subsequent secondary stresses, including insulin resistance, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and liver injury.
act, leading to the progression of NAFLD to NASH or more advanced disease stages
.
Numerous studies have attempted to identify potential molecular mechanisms and therapeutic targets for the pathogenesis of NAFLD and NASH
.
For example, mutation or inactivation of PNPLA3, TNIP3, TRAF5 or TBL1 has been shown to cause or promote NAFLD and NASH
.
The expression levels of these genes were inversely correlated with the development of NAFLD and NASH in mice and humans
.
However, the therapeutic promise of targeting these factors for the clinical management of NAFLD and NASH has not been clearly demonstrated
.
The human fibroblast growth factor (FGF) family consists of 18 members that signal in a paracrine or endocrine manner by activating cognate transmembrane FGF receptor (FGFR) tyrosine kinases
.
FGF7, FGF8, FGF9, FGF17, and FGF18 have all been shown to be paracrine factors and have roles in embryonic liver development and adult liver injury repair
.
Serum levels of endocrine FGF19 and FGF21 are associated with the development of NAFLD and NASH, and pharmacological administration of FGF19 and FGF21 prevents the pathogenic progression of NAFLD, including hepatic steatosis and NASH associated with obesity and diabetes
.
Schematic diagram of the article (figure from Hepatology) Ileum-derived FGF19 acts as a negative regulator of hepatic bile acid synthesis and a stimulator of gallbladder filling via FGFR4
.
However, in experimental mouse models, chronic, excess FGF19 promotes the development of HCC
.
In this study, FGF4, a factor unknown to act in the liver, was identified as a potentially important new regulator of liver metabolism and cellular homeostasis in mouse models and human patients
.
Deficiency of Fgf4 in hepatocytes exacerbates diet-induced NAFLD development
.
Pharmacological administration of recombinant FGF4 (rFGF4) attenuates hepatic steatosis, inflammation, and liver injury by activating the FGFR4-mediated AMPK-Caspase 6 pathway without significant side effects
.
The findings reveal new therapeutic strategies for the treatment of NAFLD and NASH
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32404
.
There is increasing evidence that several fibroblast growth factors (FGFs) play important roles in different aspects of liver pathophysiology
.
On February 12, 2022, Wenzhou Medical University Huang Zhifeng, Li Xiaokun and Chen Yongping (Song Lintao, Wang Luyao and Hou Yushu are the co-first authors) published a joint communication online in Hepatology (IF=17) entitled "FGF4 protects the liver from non -alcoholic fatty liver disease by activating the AMPK-Caspase 6 signal axis", which reports a previously unappreciated role of FGF4 in the liver
.
In human patients and mouse models, hepatic FGF4 expression was inversely correlated with NAFLD pathological grade
.
Loss of hepatic Fgf4 exacerbates hepatic steatosis and liver injury induced by an obese high-fat diet (HFD)
.
In contrast, exogenous recombinant rFGF4 was found to significantly reduce liver steatosis, inflammation, liver injury and fibrosis in NAFLD/NASH mice, thereby improving or even reversing NAFLD/NASH
.
These beneficial effects of FGF4 are mainly mediated by activation of hepatic FGFR4, which activates the downstream Ca2+-CaMKKβ-dependent AMPK-Caspase 6 signaling axis, resulting in enhanced fatty acid oxidation, reduced hepatocyte apoptosis, and reduced liver injury
.
In conclusion, this study identifies FGF4 as a novel stress response regulator of liver pathophysiology that acts through the FGFR4-AMPK-Caspase 6 signaling pathway, revealing novel strategies for the treatment of NAFLD and related liver lesions
.
Nonalcoholic fatty liver disease (NAFLD), defined as excessive lipid accumulation in the absence of chronic alcohol intake, is considered a hepatic manifestation of metabolic syndrome and can manifest as a spectrum of liver lesions ranging from simple steatosis (non-alcoholic steatosis).
Alcoholic fatty liver, NAFL), non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis to hepatocellular carcinoma (HCC)
.
NAFLD is fast becoming one of the most worrisome public health problems globally due to the increasing prevalence of obesity and diabetes
.
NASH is typically characterized by the presence of NAFL, lobular inflammation, and hepatocyte ballooning, which are important risk factors for fibrosis, which can further develop into cirrhosis and HCC
.
Despite widespread occurrence and a high risk of more severe disease, NAFLD and NASH remain without an approved drug treatment to date, creating an urgent medical need
.
The pathogenesis of NAFLD and NASH is multifactorial, with hepatic lipid accumulation and subsequent secondary stresses, including insulin resistance, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and liver injury.
act, leading to the progression of NAFLD to NASH or more advanced disease stages
.
Numerous studies have attempted to identify potential molecular mechanisms and therapeutic targets for the pathogenesis of NAFLD and NASH
.
For example, mutation or inactivation of PNPLA3, TNIP3, TRAF5 or TBL1 has been shown to cause or promote NAFLD and NASH
.
The expression levels of these genes were inversely correlated with the development of NAFLD and NASH in mice and humans
.
However, the therapeutic promise of targeting these factors for the clinical management of NAFLD and NASH has not been clearly demonstrated
.
The human fibroblast growth factor (FGF) family consists of 18 members that signal in a paracrine or endocrine manner by activating cognate transmembrane FGF receptor (FGFR) tyrosine kinases
.
FGF7, FGF8, FGF9, FGF17, and FGF18 have all been shown to be paracrine factors and have roles in embryonic liver development and adult liver injury repair
.
Serum levels of endocrine FGF19 and FGF21 are associated with the development of NAFLD and NASH, and pharmacological administration of FGF19 and FGF21 prevents the pathogenic progression of NAFLD, including hepatic steatosis and NASH associated with obesity and diabetes
.
Schematic diagram of the article (figure from Hepatology) Ileum-derived FGF19 acts as a negative regulator of hepatic bile acid synthesis and a stimulator of gallbladder filling via FGFR4
.
However, in experimental mouse models, chronic, excess FGF19 promotes the development of HCC
.
In this study, FGF4, a factor unknown to act in the liver, was identified as a potentially important new regulator of liver metabolism and cellular homeostasis in mouse models and human patients
.
Deficiency of Fgf4 in hepatocytes exacerbates diet-induced NAFLD development
.
Pharmacological administration of recombinant FGF4 (rFGF4) attenuates hepatic steatosis, inflammation, and liver injury by activating the FGFR4-mediated AMPK-Caspase 6 pathway without significant side effects
.
The findings reveal new therapeutic strategies for the treatment of NAFLD and NASH
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32404
