| First Author | He F | Year | 2022 |
| Journal | Mol Cell Endocrinol | Volume | 547 |
| Pages | 111599 | PubMed ID | 35181437 |
| Mgi Jnum | J:327460 | Mgi Id | MGI:6885407 |
| Doi | 10.1016/j.mce.2022.111599 | Citation | He F, et al. (2022) Autophagy protects against high uric acid-induced hepatic insulin resistance. Mol Cell Endocrinol 547:111599 |
| abstractText | Uric acid (UA), the end-product of purine metabolism, is closely related to hepatic insulin resistance (IR). Autophagy is a conserved intracellular degradation process maintaining cellular homeostasis. Autophagy plays a protective role in obesity-related hepatic IR, but whether it occurs in high uric acid (HUA)-induced hepatic IR is unclear. In this study, spontaneously elevated UA level induced hepatic IR and facilitated hepatic autophagy degradation in uricase knockout (Uox(-/-)) mice. In vitro, HepG2 cells stimulated with HUA medium showed decreased glucose uptake and inhibition of insulin signaling pathways, concomitant with activation of autophagy, as manifested by increased conversion of LC3B-I to -II. Rapamycin, the autophagy activator, alleviated but the autophagy inhibitor trimethyl adenine (3-MA) aggravated HUA-induced IR in HepG2 cells. Similarly, rapamycin ameliorated and 3-MA worsened HUA-induced blood glucose level and hepatic IR in Uox(-/-) mice. Mechanistically, HUA enhanced AMPKalpha phosphorylation (p-AMPKalpha) and inhibited mammalian target of rapamycin phosphorylation (p-mTOR) in HepG2 cells. The levels of p-AMPKalpha and LC3B-II/I were downregulated in HepG2 cells transfected with small interfering RNA (siRNA) against AMPKalpha, which suggests that the AMPKalpha-mTOR pathway was involved in HUA-induced autophagy. Antioxidant N-acetyl-L-cysteine reversed elevated reactive oxygen species levels induced by HUA in HepG2 cells, and AMPKalpha level was also inhibited, which suggests that AMPKalpha activation may be derived from reactive oxygen species. Collectively, these findings demonstrate that HUA increased hepatic autophagy, and autophagy activation plays a protective role in hepatic IR, which may suggest a potential therapeutic target for hepatic IR derived from HUA. |
