Hyperglycemia in Diabetes Drives Hepatic Fibrosis Through the Non-Enzymatic Function of HK2 and AGEs-mediated Matrix Stiffening.

Abstract

Diabetes is implicated in accelerating the progression of hepatic fibrosis, and empagliflozin (an SGLT2 inhibitor) has potential therapeutic effects on diabetic hepatic fibrosis. However, their underlying mechanisms are still largely uncharacterized. In this study, we found that diabetes obviously promoted hepatic fibrosis progression, and empagliflozin intervention effectively impeded this pathological process independent of its hypoglycemic effects. Mechanistically, high glucose stimulation significantly increased HSC activation and its metabolic enzyme HK2 dissociation from mitochondria. The dissociated HK2 interacted with STAT3 to increase its nuclear entry for upregulating HSC activation-associated gene expression. Meanwhile, high glucose stimulation also suppressed KLF4 expression to attenuate its inhibitory effect on STAT3 transcription activation in HSCs. Additionally, high glucose-induced AGEs accumulation resulted in matrix stiffening, which also increased HSC activation. Empagliflozin alleviated hepatic fibrosis progression through decreasing AGEs accumulation and suppressing STAT3 and FOXO1 phosphorylation in HSCs. From the new perspectives of the non-metabolic functions of metabolic enzymes and matrix biomechanics, this study sheds light on a new synergistic regulatory pathway through which diabetes promotes hepatic fibrosis and highlights empagliflozin as a potential therapeutic agent for diabetic hepatic fibrosis.