ANGPTL8 in metabolic homeostasis: more friend than foe?

Figure 1.. Regulation of ANGPTL8 expression during fasting/fed. Under feeding conditions, the increase of insulin, glucose and FA can increase the expression of ANGPTL8 through a variety of pathways. PI3K/Akt, LXRα, ChREBP, SREBP-1c, C/REBPβ, HNF-1α and VDR may participate in this process. Under fasting condition, GR signal inhibited the transcription of ANGPTL8. At the same time, PPARα competes with LXR to bind to RXR, which inhibits the induction of ANGPTL8 expression by LXR.

Figure 2.. The directing effect of ANGPTL8 on TG during fasting/fed. (a) Under the fasting condition, the expression of ANGPTL4 increased, while the expression of ANGPTL8 decreased in WAT, which enhanced the inhibition of LPL activity and decreased the uptake of TG by WAT. At the same time, the active lipolysis in WAT results in the release of FA. The decrease of circulating ANGPTL3/8 complex alleviated the inhibition of LPL activity in muscle tissue, and the muscle obtained more energy substrates. (b) Under the feeding condition, the circulating ANGPTL3/8 complex increased and the local LPL activity in muscle tissue was significantly inhibited. At the same time, the expression of ANGPTL4 decreased in WAT, and the formation of ANGPTL3/4 complex weakened the inhibitory effect of ANGPTL4 on LPL. As a result, more TG is directed into WAT for storage.

Figure 3.. Compensatory increase of ANGPTL8 in pathological state improves metabolism. Insulin resistance occurs in the pathological state of diabetes and obesity, which leads to a variety of metabolic disorders in liver, fat and muscle. Hyperinsulinaemia, glucose, FA and stress induced compensatory increase of ANGPTL8. ANGPTL8 not only improves insulin sensitivity by enhancing Akt phosphorylation, but also enhances the storage and buffering capacity of WAT, reducing the damage of ectopic lipid pile and lipid toxicity in other tissues.