In the last few years exciting discoveries support a role for fibroblast growth factor 21 (FGF21) as a metabolic target. FGF21 is a member of an atypical subfamily of FGFs, including FGF15/19 and FGF23, that can circulate as hormones because they do not possess heparin-binding properties, enabling them to be released into the circulation.[1, 2] Nuclear receptors, nutritional stimuli, and hormones participate in the transcriptional regulation of the FGF21 gene. Hepatic FGF21 gene transcription is promoted by ketogenic diet, fasting, nonesterified fatty acid (NEFA), and fenofibrate. FGF21 expression is regulated directly by peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor activated by specific fatty acids and the fibrate class of hypolipidemic drugs. FGF21 acts through a cell surface receptor complex composed of conventional FGF receptor 1c and βKlotho. The binding between FGF21 and its receptors activates FGF receptors substrate 2α and ERK1/2 phosphorylation. Liver, pancreas, and adipose tissue are the main organs on which FGF21 exerts its action. In the liver, FGF21 acts as an endocrine hormone to govern and coordinate the adaptive response during starvation, while functioning as an autocrine fed state factor in the white adipose tissue (WAT), to regulate adipocyte function and gene expression. In the fasted state or in response to fibrate drugs, FGF21 behaves as an endocrine hormone to increase adipose tissue lipolysis and hepatic ketogenesis and gluconeogenesis, increasing circulating β-hydroxybutyrate and reducing glucose, insulin, and cholesterol levels.[5, 6]
Furthermore, FGF21 metabolic actions include growth hormone resistance and induction of torpor (a state characterized by physical inactivity and low body temperature). Unlike glucagon, FGF21 does not promote glycogenolysis. In response to feeding or thiazolidinedione drugs (TZD, a potent PPARγ agonist), FGF21 works in WAT through an autocrine mechanism to stimulate PPARγ activities and thermogenic response. In obese rodents and monkey, FGF21 administration improves insulin sensitivity, normalized triglyceride, and cholesterol levels and causes weight loss. In a recent work, it has been demonstrated that cold temperature exposure increased circulating FGF21 and treatment with this hormone up-regulates human adipocyte brown fat gene and thermogenesis in a specific manner.
FGF21 is a potential therapeutic target since it controls glucose and lipid metabolism in response to nutritional stress and in a tissue-specific manner. It has been demonstrated that high levels of FGF21 protein reduce glycemia and that circulating FGF21 levels were found increased in obese human subjects or who have type 2 diabetes, impaired glucose tolerance, or NEFA. This conundrum might be explained by the fact that FGF21 secretion could eventually represent a response of the organism to cope with obesity and metabolic syndrome. Indeed, the insulin mimetic properties of FGF21 make it a potential target in weight control and to improve the metabolic profile.
In this issue of Hepatology, Ye et al. elucidated the role of FGF21 in acetaminophen (APAP)-induced hepatotoxicity, suggesting an interesting mechanism of action. Several in vivo studies have demonstrated the beneficial effect of FGF21 in cerulean-induced pancreatitis and sepsis but the importance of this hormone in APAP-induced acute liver failure has never been examined to date. By administration of APAP in wild-type mice, the authors demonstrated an increase of serum FGF21 at 3 hours after drug injection with a peak level at 6 hours and a decline to basal level at 24 hours. Furthermore, FGF21 protein and gene expression in response to APAP is hepatic-specific and PPARα-independent. Intriguingly, it has been observed that serum alanine transaminase (ALT) levels, a liver injury marker, started to increase when serum FGF21 levels decline to its baseline after APAP treatment, suggesting that serum FGF21 can be consider an early biomarker of APAP-induced liver injury.
Using FGF21 knockout (KO) mice treated with APAP, Ye et al. provided evidence of a protective role of this hormone in APAP hepatotoxicity and mortality, demonstrating that the increase of FGF21 represents a compensatory response of the liver to defend against APAP-induced liver damage.
APAP overdose causes glutathione reduction, mitochondrial dysfunction, and oxidative stress by an increase of Jun-N-terminal kinase (JNK) phosphorylation. FGF21 KO mice showed a marked increase of hepatic reactive oxygen species (ROS) production, lipid peroxidation, and JNK phosphorylation due to a defective ROS scavenging system. The authors show that FGF21 treatment prevents APAP hepatotoxicity by restoring the liver antioxidant activity.
Of note, when FGF21 KO mice were treated with APAP followed by injection with recombinant mouse FGF21, they showed a reduction in ALT and aspartate aminotransferase (AST) levels, in liver necrosis and in hepatic ROS accumulation. As compensatory response to oxidative stress the antioxidant system is activated to protect cell damage.
FGF21 is able to act as an upstream inducer of peroxisome proliferator-activated receptor coactivator protein 1α (PGC1α), a transcriptional coactivator that regulates the expression of many antioxidant genes including the nuclear factor erythroid 2-related factor 2 (nrf2). The expression of PGC1α and nrf2 were markedly reduced in APAP-treated FGF21 KO. To close the circle, the authors evaluated whether the induction of PGC1α is necessary for the FGF21 protective effects in APAP-induced liver damage using FGF21 KO mice treated with small interfering RNA (siRNA) against PGC1α. In these mice APAP induced a significant increase of ALT and AST, several necrosis areas in liver sections, ROS accumulation, and a reduced expression of nrf2, suggesting that the induction of nrf2 is a downstream event of PGC1α in response to FGF21 stimulation. The overexpression of PGC1α is sufficient to reverse the increased susceptibility of FGF21 KO mice to APAP-induced liver injury.
Ye et al. identified a new biomarker of APAP-induced hepatotoxicity earlier than AST and ALT, classic liver injury markers used in clinical practice. This new discovery confirms the potential role of FGF21 as a therapeutic target. Moreover, the authors shed light on APAP-induced liver toxicity, showing that elevation of FGF21 may represent a compensatory mechanism to adaptive response.
The study showed that a drastic elevation in FGF21 production occurs in the APAP-induced liver damage. The increase of this hormone is able to trigger antioxidant genes expression in order to decrease mitochondrial oxidative stress through the reduction of ROS that promote hepatocytes necrosis and liver toxicity. These processes arise from the induction of expression of PGC1α, which in turn activates nrf2-mediated expression of antioxidant genes (Fig. 1). Of note, the induction of PGC1α by FGF21 has a key role in mediating FGF21-induced gluconeogenesis and fatty acid oxidation in hepatocytes and mitochondrial biogenesis in adipocytes. FGF21 induces the expression of the transcriptional coactivator protein PGC1α in the liver and WAT. Indeed, PGC1α may represent an indispensable effector of metabolic actions of FGF21. Intriguingly, Ye et al. in an ex vivo experiment demonstrated that recombinant mouse FGF21 was unable to promote the expression of PGC1α and its downstream target genes in isolated primary hepatocyte, suggesting that the induction of hepatic PGC1α by FGF21 may require an additional factor that is lost in primary hepatocyte cells. Thus, in primary hepatocytes FGF21 per se is not able to determine the protective response APAP induced in the entire liver, while PGC1α is certainly an indispensable factor to trigger the production of antioxidant genes. From a mechanistic point of view, an important question that remains is how the liver produces FGF21 under APAP-induced acute injury. Could the xenobiotic nuclear receptor PXR-CAR be involved? This elegant piece of work promotes FGF21 within the players in the battle against liver injury induced by APAP. To date, the therapeutic options for APAP-induced hepatotoxicity are rather limited and FGF21 might play an important role in new clinical solutions.
Marica Cariello, Ph.D.
Antonio Moschetta, M.D., Ph.D.
National Cancer Research Center IRCCS Oncologico Giovanni Paolo II Bari, Italy Interdisciplinary Department of Medicine University of Bari, Italy