• LIVER
• NONALCOHOLIC STEATOHEPATITIS
• FATTY LIVER

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease in the Western countries affecting 20%–30% of the general population. NAFLD is considered as one of the manifestations of the metabolic syndrome, closely associated with obesity and type 2 diabetes, and may range from steatosis to the more aggressive form of non-alcoholic steatohepatitis (NASH). Long-standing NASH may progress in severe form of liver diseases, such as cirrhosis and hepatocellular carcinoma.

Steatosis in the liver is characterised by a large intracytoplasmic or well-defined fat droplets accumulation, displacing the nucleus to the cell periphery. Abnormal hepatic triglyceride accumulation is due to dysregulation of fatty acid metabolism. In healthy conditions, fatty acids are preferably stored in adipose tissue. However, elevated peripheral fatty acids together with hepatic de novo lipogenesis and defective apolipoprotein biosynthesis lead to hepatic lipid accumulation.

In this issue, Guillou and colleagues identify a novel hepatic-specific mechanism in the pathogenesis of NAFLD that directly involves the fatty acid sensor peroxisome proliferation-activated receptor α (PPARα) and the hormone fibroblast growth factor 21 (FGF21).1

PPARs are ligand-activated transcription factors belonging to the nuclear receptor subfamily. They act as lipid sensors, regulating almost every aspect of lipid metabolism. Functional impairment or dysregulation of these receptors leads to obesity, fatty liver and type 2 diabetes. Although the three PPAR isoforms (α, β/δ and γ) share structural similarity and high homology sequence, they are differentially expressed among tissues. PPARα is highly expressed in metabolically active tissue. However, the in vivo effects of PPARα agonist are mainly evident in the liver.

PPARα regulates the expression of genes involved in fatty acid catabolism, including genes for hepatic clearance of very low density lipoprotein, fatty acid uptake and oxidation. PPARα-null mice display a fatty liver phenotype resulting from a decreased expression of fatty acid oxidation genes.2 PPARα is induced during fasting and is required for ketogenesis. In fact, PPARα-null mice in a fasted state show a severe fatty liver phenotype, characterised by low plasmatic level of glucose and ketonic bodies and high level of free fatty acids, together with loss of induction of hepatic fatty acid oxidation genes. Moreover, pharmacological PPARα activation concomitant to high-fat, low-carbohydrate ketogenic diet leads to upregulated expression and plasmatic levels of FGF21.3 FGF21 acts as an endocrine hormone, exerting its metabolic effects mostly in the liver, adipose tissue and pancreas. Further studies identified FGF21 as a direct PPARα target gene, induced by fasting or in the presence of PPARα ligands. FGF21-null mice display impaired hepatic expression of fatty acid oxidation genes and ketogenesis, providing a strong evidence for FGF21 requirement in the regulation of this pathway.3 Indeed, the introduction of FGF21 in PPAR-null mice partially rescues ketonaemia and fatty liver. Tissue-selective FGF21 signalling requires coreceptor β-klotho and one of the FGF receptors (FGFRs), mostly FGFR1c.4 In adipose tissue, FGF21 regulates the expression of lipases important for fatty acid release and a subset of PPARα target genes directly involved in fatty acid oxidation. Moreover, it acts as an adipokine by stimulating glucose uptake by white adipose tissue (WAT) and brown adipose tissue and triggering WAT browning.5 It has been recently shown that FGF21 mediates the starvation response affecting the peripheral metabolism and acting directly on the central nervous system, increasing systemic glucocorticoid levels, suppressing physical activity and altering the circadian behaviour.6 In the brain, FGF21 stimulates the hypothalamic pituitary-adrenal axis, thus facilitating corticosterone release and stimulating gluconeogenesis in the liver.7 In addition, in different obese murine models the brain signals to the adipose tissue to induce lipolysis and glucose uptake via FGF21-mediated enhancement of sympathetic nerve activity.8

The PPARα-FGF21 axis plays a key role in the homeostasis of fatty acid metabolism across a broad spectrum of organs. Dysregulation of this pathway can lead to liver disease, especially to NAFLD. In the present work, Guillou and colleagues exploit the role of hepatic PPARα in liver homeostasis. They deepen our understanding on PPARα function in the whole-body metabolism regulation, providing new insight in the pathogenesis of NAFLD. Previous studies indicated that the whole-body PPARα ablation is effectively related to severe form of steatosis. Here the authors demonstrate that hepatic-specific ablation of PPARα induces susceptibility to fatty liver. They show that hepatocyte-restricted PPARα deletion during fasting, methionine choline-deficient-diet feeding or ageing represents a pivotal point in the progression of steatosis. Also, hepatic PPARα is responsible for the control of circulating lipids, thus its absence results in hypercholesterolaemia. They propose that free fatty acids released from adipocytes during chronic or acute lipolysis activates the hepatic PPARα response, defining a central role for hepatocyte-specific PPARα in the control of liver and whole-body fatty acid homeostasis. In term of possible mechanism, Guillou and colleagues evaluate the role of a direct PPARα target gene, FGF21. Previously it was described that PPARα-null mice are FGF21 deficient, displaying a compromised phenotype during ketosis, and the restoration of FGF21 level partially reverse the hypertriglyceridaemia and hypoketonaemia observed in fasted PPARα-null mice.3 Guillou et al prove that the absence of FGF21 is not the primary cause for steatosis observed in liver-specific PPARα-null mice. Previous results indicate that FGF21 is fundamental in the prevention of liver steatosis.

Guillou et al reveal a new intriguing aspect of PPARα-FGF21 axis, elucidating how PPARα controls FGF21. In particular, they evaluate the circadian kinetics of FGF21 showing a constitutive peak early in the morning and a fasting-dependent peak during the night. Surprisingly, the FGF21 kinetic is perfectly overlapping the circadian PPARα mRNA rhythm, suggesting a fine PPARα-dependent FGF21 tuning. Moreover, the regulation of hepatic PPARα by adipose-derived signal is time restricted with a peak of activity early in the night. Taken together, these results suggest the existence of an insulin-sensitive signalling mechanism influencing adipocytes lipolysis and hepatic PPARα expression. Considering FGF21 as an insulin sensitiser, it would be interesting to unravel whether it can play different roles depending on different metabolic status.9 For example, a specific metabolic adaptation mediated through FGF21 action on the central nervous system has been previously described.6 FGF21 action in the brain has several effects on distal tissues, influencing metabolism, behaviour and reproduction, and resulting in a fine-tune interorgan crosstalk.8 ,10 Guillou et al evaluate the FGF21 endocrine effects on whole-body glucose homeostasis and thermogenesis. Hepatic-specific PPARα knockout mice show less severe hypoglycaemia and hypothermia compared with PPARα-null mice, indicating that extrahepatocytic PPARα strongly influences glucose homeostasis and body temperature. Thus, it remains to clarify how FGF21 can act in concert with different pathways, providing a refined coordination of circadian rhythms and whole-body homeostasis. The present study highlights the PPARα roles specific in the liver and its coordinate action with FGF21 in the whole-body fatty acid homeostasis, confirming the role of this hormone in the nexus between different pathway, thus paving way for the development of new therapies for obesity and NAFLD.