Reply.

Abstract

We thank H.-H. Chung for his interest in our NAFLD study showing that hepatocyte PAR2 promotes impaired glucose uptake by suppressing the glucose transporter GLUT2 and triggers insulin resistance through an Akt interference mechanism.1 These effects could be effectively reversed in severely diabetic mice with a liver-homing PAR2 pepducin or by liver-specific knock-out of PAR2. Dr. Chung brings up the point that global PAR2-deficient mice fed high-fat diet in a nondiabetic model had drops in liver mRNA levels for genes involved in gluconeogenesis (G6P, PEPCK) and lipogenesis (SREBP-1c, FAS) which could conceivably contribute to improving insulin resistance.2 We had previously demonstrated that nondiabetic PAR2-deficient mice fed high-fat diet had significant reductions in nuclear translocation of active SREBP-1c in liver cells that occurred via a PAR2-JNK mechanism.3 Using liver and plasma metabolomics, we also documented that these same PAR2-deficient mice had major increases in β-oxidation of fatty acids and a marked ketogenic shift in liver metabolism resulting in efficient fat breakdown and suppression of obesity.3 Despite lower circulating glucose, liver glucose and glycogen concentrations were significantly elevated indicating suppression of hepatic glycolysis rather than suppression of gluconeogenesis. In fact, these observations led to the current paper that showed that PAR2 deficiency improved glycemic parameters and increased liver glucose uptake and glycogenesis independent of obesity or diabetic status.1 Consistent with the interesting observation by Dr. Chung that PAR2 regulation of adipokines may be liver-specific, our previous work revealed that the PAR2-deficient mice fed high-fat diet had major increases in mRNA expression of the hepatokine FGF21, a signaling molecule induced in ketotic states.3 With regards to the association of PAR2 with AMPK and autophagy through enhanced interaction of CaMKK2 and β-arrestin in HepG2 cells, this is an excellent hypothesis that requires further evaluation in NAFLD and liver metabolism and could be related to our newly described CaMMK2-β-arrestin interference mechanism on insulin-Akt signaling.1 Indeed, we had previously found that PAR2 deficiency caused enhanced AMPK activation in NAFLD livers along with significant upregulation of AMPK targets Pgc1α, Pgc1β, and PPARα.3 AMPK is a master regulator of hepatic insulin resistance and disruption of AMPK would worsen hepatic steatosis and induce NASH. To the extent that PAR2 attenuates the activity of AMPK, a PAR2 inhibitor has the potential to improve NAFLD/NASH as well as other sequelae of metabolic syndrome. This is definitely a high-impact avenue worth pursuing in future clinical trials.