Redox Biology
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2026
·
IF 16.2
Meiling Wu,Qiwen Luo,Sheng Ge,Lihan Jiang,Kelei Dong,Fulin Zhang,Wanrui Fu,Bo Feng,Liang Qiao,Shanlin Liu,Dongyun Shi
Sustained upregulation of hepatic gluconeogenesis is a major source of hyperglycemia in type 2 diabetes, and obesity is the primary driver. However, a substantial subset of obese individuals does not progress to diabetes, a condition termed metabolically healthy obesity, and the underlying mechanism has long remained unclear. ROS act both as physiological signals and as pathological drivers, but no molecular marker characterizes the transition between these two states, making it difficult to time antioxidant intervention against oxidative modification-mediated damage. Here we show that the activity of phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme of gluconeogenesis, is redox-sensitive. Excess accumulated ROS induces reversible sulfenylation at cysteine 288, near the catalytic center, directly driving gluconeogenesis in the absence of insulin. We therefore propose a dual regulatory model of glucose metabolism signaled by hepatic oxidative load. At low oxidative load, ROS activates AMP-activated protein kinase (AMPK) via glutathionylation to promote glycolysis, whereas once the load accumulates, PCK1 is activated via sulfenylation to drive gluconeogenesis, accompanied by a decline in AMPK glutathionylation. Hepatic oxidative load therefore acts as a switch governing the direction of hepatic glucose flux. In diabetic mice, the two modifications show a complementary, stage-dependent distribution paralleling this accumulation, with AMPK glutathionylation predominating in the compensatory stage and PCK1 sulfenylation becoming dominant as the load accumulates further. Their reciprocal dynamic therefore serves as an early warning signal for the transition of ROS from physiological to pathological states. On this basis, we intervened as oxidative load began to accumulate, and found that lowering hepatic ROS prevented the oxidative activation of PCK1, suppressed gluconeogenesis and ameliorated hyperglycemia. These findings reveal that the key gluconeogenic enzyme is directly regulated by redox signals independently of insulin, providing a molecular basis for the heterogeneity of diabetes progression in obesity and for the precise timing of antioxidant intervention. Download: Download high-res image (223KB) Download: Download full-size image
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DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2025
·Vol. 1872
·期 3
·168106
·
IF 4.2
Xiaoyi Sun,Chunlin Gao,Pei Zhang,Yingchao Peng,Meiqiu Wang,Jiuyu Liu,Chenxi Ma,Shan Li,Zhengkun Xia
Kidney stone disease (KSD) is one of the most common urological disorders, and oxalate-induced tubular epithelial cell injury plays a crucial role in stone-related renal damage. However, the mechanisms linking oxalate exposure to mitochondrial dysfunction remain unclear. Urolithin A (UA), a gut microbiota–derived metabolite of ellagitannins, is recognized for its antioxidant and mitophagy-promoting properties. This study investigated the renoprotective effects and mechanisms of UA in calcium oxalate (CaOx) crystal–induced renal injury. In mice, UA markedly reduced renal CaOx deposition, improved renal function, and alleviated kidney injury. Consistently, both in vivo and in vitro experiments demonstrated that UA restored oxalate-suppressed mitophagy while also alleviating oxidative stress, apoptosis, and mitochondrial dysfunction. Transcriptomic and molecular docking analyses identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a downstream target of UA. UA restored PCK1 expression under oxalate stress both in vivo and in vitro, whereas pharmacological inhibition of PCK1 weakened the renal protective and mitophagy-promoting effects. Conversely, PCK1 overexpression enhanced mitophagy under high-oxalate conditions. These findings indicate that UA alleviates CaOx-induced renal injury by activating PCK1-dependent mitophagy and restoring mitochondrial homeostasis. Given its natural origin and favorable safety profile, UA represents a promising candidate for preventing or treating calcium oxalate–associated renal injury.
研究领域:
肾脏病学
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分子生物学
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代谢学
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泌尿科学
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线粒体生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2023
·Vol. 14
·期 3
·1674-1684
·
IF 6.1
Jingqi Zhao,Yantong Sun,Cuiping Yuan,Tiezhu Li,Yuan Liang,Haoyang Zou,Jie Zhang,Li Ren
As a natural pigment in food, quercetin possesses multiple biological activities and plays a crucial role in regulating metabolic syndrome. Herein, we aim to explore the potential mechanism of quercetin to ameliorate hepatic fat accumulation. In vivo experiments showed that quercetin significantly relieved inflammation response by decreasing the serum TNF-α and IL-6 levels and also improved high-fat diet-induced hepatic steatosis without other organ injuries. Quercetin can effectively reduce lipid aggregation and down-regulate the protein expression of PCK1 in HepG2 cells induced by oleic acid and palmitic acid, indicating that inhibiting gluconeogenesis leads to hepatic fat accumulation reduction. Furthermore, molecular docking results suggested that quercetin can bind to both PPARα and PPARγ, with an even more potent binding affinity than indeglitazar, a pan-agonist of PPARs. In conclusion, quercetin may regulate gluconeogenesis to ameliorate hepatic fat accumulation via targeting PPARα/γ.
研究领域:
药理学
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代谢学
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营养学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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