Effects of Ageing, Diet and PKM2 Manipulation in Myeloid Cells on MAFLD Progression

Abstract

MAFLD has a 30% global prevalence with no approved therapy. This results in the increase of the global burden of the complications (e.g., liver cancer and CVD). The liver disease has been shown to be a complex disease influenced by genetic and environmental (e.g.,dietary) factors. In addition, the prevalence of MAFLD has been seen to be higher in ageing population, and this has been attributed to senescence in hepatocytes that have shown less fitness when exposed to overnutrition. These factors cause hepatic lipid accumulation that is followed by lipotoxicity and hepatic inflammation. Therefore, MAFLD pathogenesis can be summarised by the activation of immune response by metabolic dysregulation. These arguments have supported the concept that dysregulation in immunometabolism is the foundation of MAFLD pathogenesis.

Immunometabolism is reflected in the behaviour of liver microenvironment. In liver microenvironment, metabolic zonation results in the heterogeneity of hepatocytes. The heterogeneity maintains liver homeostasis. When the homeostasis is perturbed by various causes (e.g., lipotoxicity), hepatocytes show their ability to initiate immune response. The immune response is reverberated through the behaviour of resident and infiltrating liver immune cells.

The valuable insight from network medicine has shown that MAFLD is a complex disease that stems from the perturbation of immunometabolism. In the previous studies, PKM was shown to be a core gene that connected metabolism and immune response. PKM is a gene that encodes PKM2 and of late, PKM2 has become an important target in immunometabolism. It also has shown its remarkable capacity to metabolically reprogram myeloid cells.

We hypothesised that targeting PKM2 in myeloid cells would influence the behaviour of immune response. The immune response behaviour of immune cells could be seen further in their response to environmental stimuli in the liver microenvironment.