Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress

Abstract

BackgroundFGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.MethodsIn this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.ResultsWe found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.ConclusionFGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

“…29,30 We found that S-FGF21 correlated with prohormone brain natriuretic peptide and ejection fraction %, suggesting that heart failure could induce FGF21. Despite reports of increased expression of FGF21 in the liver in hepatic stress and hepatocarcinogenesis in mice and humans, 31 we found no S-FGF21 increase in liver pathology (mCRC, PBC, PSC), nor did it associate with liver dysfunction tests or degree of atypia in biliary tracts, indicating that FGF21 is not a general consequence of liver disease. Poor disease prognosis or general frailty did not stimulate S-FGF21.…”

A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation

“…13) Among them, FGF21 is a hepatokine mainly expressed in the liver tissue. 10) Many studies have revealed FGF21 as a mediator of pleiotropic actions of PPARα. 18,19) Our previous study conducted in an obese mouse model revealed that MHY2013 increased FGF21 levels in the liver and serum.…”

“…[7][8][9] In addition, it directly upregulates the expression of the hepatokine, fibroblast growth factor 21 (FGF21), which is considered a promising intervention target for metabolic diseases owing to its insulin-sensitizing and thermogenesis-inducing effects. 10) However, PPARγ is predominantly expressed in the adipose tissue, where it regulates adipocyte differentiation and insulin sensitivity. 7,8) PPARγ is a key regulator of adiponectin, a well-known insulin sensitizer.…”

Targeting FGF19 binding to its receptor system: A novel therapeutic approach for hepatocellular carcinoma

“…Amplifications of FGF19 in HCC have been reported in several genomics studies. 1,3,4 Recent studies have demonstrated that FGF19 plays key roles in hepatocarcinogenesis. 5 Genetic aberrations in FGF21 have not been reported in liver cancer genomics studies.…”

“…2 Interestingly, FGF21 was overexpressed in HCC. 1,3,4 It should be very interesting to assess if, from the data set of genome-wide analysis, HCC samples in which FGF19 high copy amplifications overlap with copy number variations or single mutations localized at 19q13.33 containing the FGF21 gene may emerge. This could be very relevant to understanding if an anti-FGF19 strategy may be potentially sufficient as a therapeutic approach.…”