Hepatoprotective Effect of Quercetin on Endoplasmic Reticulum Stress and Inflammation after Intense Exercise in Mice through Phosphoinositide 3-Kinase and Nuclear Factor-Kappa B

Abstract EN

The mechanisms underlying intense exercise-induced liver damage and its potential treatments remain unclear.

We explored the hepatoprotection and mechanisms of quercetin, a naturally occurring flavonoid, in strenuous exercise-derived endoplasmic reticulum stress (ERS) and inflammation.

Intense exercise (28 m/min at a 5° slope for 90 min) resulted in the leakage of aminotransferases in the BALB/C mice.

The hepatic ultrastructural malformations and oxidative stress levels were attenuated by quercetin (100 mg/kg·bw).

Intense exercise and thapsigargin- (Tg-) induced ERS (glucose-regulated protein 78, GRP78) and inflammatory cytokines levels (IL-6 and TNF-α) were decreased with quercetin.

Furthermore, quercetin resulted in phosphoinositide 3-kinase (PI3K) induction, Ca2+ restoration, and blockade of the activities of Jun N-terminal kinase (JNK), activating transcription factor 6 (ATF6) and especially NF-κB (p65 and p50 nuclear translocation).

A PI3K inhibitor abrogated the protection of quercetin on ERS and inflammation of mouse hepatocytes.

SP600125 (JNK inhibitor), AEBSF (ATF6 inhibitor), and especially PDTC (NF-κB inhibitor) enhanced the quercetin-induced protection against Tg stimulation.

Collectively, intense exercise-induced ERS and inflammation were attenuated by quercetin.

PI3K/Akt activation and JNK, ATF6, and especially NF-κB suppression were involved in the protection.

Our results highlight a novel preventive strategy for treating ERS and inflammation-mediated liver damage induced by intense exercise using natural phytochemicals.