Hepatokines and hepatic lipids: interaction with exercise, diet and metabolic health

Non-alcoholic fatty liver disease (NAFLD) is associated with several metabolic comorbidities, and the excessive accumulation of hepatic lipids is strongly related to both hepatic and peripheral insulin resistance. The mechanisms underpinning the link between metabolic dysfunction and NAFLD, however, are not fully understood. Hepatokines such as fibroblast growth factor 21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B and selenoprotein P (SeP) have been identified as liver-secreted factors which may influence metabolic homeostasis in distal tissues. Energy balance plays a key role in the regulation of these hepatokines and further research is required in humans to determine the responsiveness of these proteins to acute exercise and dietary interventions. Hepatic lipid composition, which can now be assessed using proton magnetic resonance spectroscopy (1H- MRS), has also been highlighted as a potential factor impacting metabolic health in NAFLD. A hepatic lipid profile consisting of more saturated and less polyunsaturated lipids is thought to be more metabolically harmful, and the relationship between hepatic lipid composition and metabolic dysfunction in NAFLD requires further characterisation.

Chapter 3 of this thesis demonstrates that a single bout of continuous, aerobic exercise transiently increases circulating FGF21 and follistatin concentrations in healthy men; with the FGF21 response being intensity-dependent. Chapters 4 and 5 show that circulating concentrations of FGF21, LECT2 and fetuin-A are elevated following short-term (1-7 days), high-fat overfeeding in healthy men; however, the time-course varies considerably between hepatokines. Specifically, the FGF21 response is rapid and transient; whilst the LECT2 response is more gradual and sustained over seven days. Initial increases in circulating fetuin- A may also begin to occur after seven days. Chapter 6 demonstrates that 1H-MRS at 3.0 tesla is a valid tool to non-invasively assess hepatic lipid composition in NAFLD; however, the technique may not be suitable for fat fractions below 5.56%. Using this methodology, Chapter 7 found that in men with NAFLD, the hepatic lipid composition of individuals with impaired glucose regulation consists of a greater proportion of saturated and a lower proportion of unsaturated/polyunsaturated lipids compared to individuals with normal glucose regulation. Furthermore, this hepatic lipid profile is associated with a lower cardiorespiratory fitness and lower levels of daily physical activity.

Collectively, the studies in this thesis demonstrate that hepatokines such as FGF21, follistatin, LECT2 and fetuin-A are sensitive to acute perturbations in energy balance induced through exercise and/or overnutrition. Furthermore, H-MRS is a valid tool to assess hepatic lipid composition in NAFLD, which appears to be more saturated and less polyunsaturated in those with impaired glucose regulation compared to those with normal glucose regulation. These findings may support a potential a role of these two factors (i.e. hepatokines and hepatic lipid composition) in the link between NAFLD and impaired metabolic health; however, further experimental evidence in humans is required. Future research should investigate the impact of more chronic lifestyle interventions on these factors to explore their potential as therapeutic targets for improving metabolic health in NAFLD.