Letter to the Editor: The pathological impact of PAR2 on hepatic insulin resistance.

Abstract

To the editor, Hepatic insulin resistance was correlated with diabetes and the progression of NAFLD. In the latest article published by Shearer et al.,1 the authors have demonstrated that protease-activated receptor 2 (PAR2) exerted impaired glucose uptake, glycogen storage, and insulin resistance by the suppression of the major hepatic glucose transporter, GLUT2, through Gq-MAPK-FoxA3 and the inhibition of insulin-Akt signaling through Gq-calcium-CaMKK2 pathways, which were reversed by a liver-homing pepducin, PZ-235. Nevertheless, I have some insights concerning the pathological mechanisms of PAR2 in hepatic insulin resistance. First, the current study mainly investigated the influence of PAR2 on hepatic glycogen synthesis but not hepatic gluconeogenesis and lipid metabolism. Notably, the expressions of G6Pase, PEPCK, SREBP-1c, and FAS involved in gluconeogenesis and lipogenesis were reduced in HFD-fed Par2−/− mice.2 Thus, enhanced hepatic glycogen synthesis and suppressed hepatic gluconeogenesis and lipogenesis by inhibiting PAR2 contributed to alleviating hepatic insulin resistance. Second, PAR2-mediated hepatic insulin resistance regarding adipokines was not mentioned, including leptin and adiponectin. Compared with wild-type mice, Db/Db mice had higher PAR2 expressions in liver but no alteration in visceral white adipose tissues in the current study, suggesting PAR2-mediated hepatic insulin resistance related to leptin signaling was liver-specific. In addition, PAR2 expressions were increased in human adipose tissues from obese people compared with lean people, and the reduced adiponection expressions in diet-induced obesity linked to adipose tissue inflammation were reversed by the PAR2 antagonist.3 Thus, the adipokines involved in PAR2-mediated hepatic insulin resistance and metabolic inflammation should be clarified. Third, the role of PAR2 in the modulation of energy utilization is worthwhile to further explore. Because hepatic insulin resistance was associated with the disruption of AMPK activation in NAFLD, PAR2 overexpression in HepG2 cells significantly attenuated AMPK-mediated autophagy and promoted palmitic acid-induced lipid accumulation through enhanced interaction of CAMKKβ with β-arrestin-2.4 Thus, AMPK activity in PAR2-mediated hepatic insulin resistance should be considered. Collectively, the higher expressions of PAR2 serve as the biomarker for the evaluation of hepatic insulin resistance, and how to clarify the pathological mechanisms of PAR2 activation is helpful for us to identify selective PAR2 modulators to improve hepatic insulin resistance associated with diabetes and NAFLD progression.