Laboratory of Molecular Nutrition for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan, China.
Lady Davis Institute for Medical Research and Department of Medicine, McGill University, Montreal, Canada.
Antioxid Redox Signal. 2022 Sep;37(7-9):417-436. doi: 10.1089/ars.2021.0190. Epub 2022 Jul 12.
Excessive manganese (Mn) exposure is toxic, and induces lipid deposition, but the underlying mechanisms remain elusive. Herein, we explored how dietary Mn supplementation affects lipid deposition and metabolism in the intestine of vertebrates using the yellow catfish as the model. High-Mn (H-Mn) diet increased intestinal Mn content, promoted lipid accumulation and lipogenesis, and inhibited lipolysis. In addition, it induced oxidative stress, upregulated metal-response element-binding transcription factor-1 (MTF-1), and peroxisome proliferator-activated receptor gamma (PPARγ) protein expression in the nucleus, induced PPARγ acetylation, and the interaction between PPARγ and retinoid X receptor alpha (RXRα), while it downregulated sirtuin 1 (SIRT1) expression and activity. Mechanistically, Mn activated the MTF-1/divalent metal transporter 1 (DMT1) pathway, increased Mn accumulation in the mitochondria, and induced oxidative stress. This in turn promoted lipid deposition deacetylation of PPARγ at K339 by SIRT1. Subsequently, PPARγ mediated Mn-induced lipid accumulation through transcriptionally activating fatty acid translocase, stearoyl-CoA desaturase 1, and perilipin 2 promoters. These studies uncover a previously unknown mechanism by which Mn induces lipid deposition in the intestine the oxidative stress-SIRT1-PPARγ pathway. High dietary Mn intake activates MTF-1/DMT1 and oxidative stress pathways. Oxidative stress-mediated PPARγ deacetylation at K339 site contributes to increased lipid accumulation. Our results provided a direct link between Mn and lipid metabolism the oxidative stress-SIRT1-PPARγ axis. . 37, 417-436.
过量的锰（Mn）暴露是有毒的，并诱导脂质沉积，但潜在的机制仍不清楚。在此，我们以黄颡鱼为模型，探索了膳食 Mn 补充如何影响脊椎动物肠道中的脂质沉积和代谢。高 Mn（H-Mn）饮食增加了肠道 Mn 含量，促进了脂质积累和脂肪生成，并抑制了脂肪分解。此外，它还诱导了氧化应激，上调了核内金属反应元件结合转录因子-1（MTF-1）和过氧化物酶体增殖物激活受体γ（PPARγ）蛋白表达，诱导了 PPARγ 乙酰化和 PPARγ 与视黄酸 X 受体α（RXRα）的相互作用，同时下调了 SIRT1 表达和活性。从机制上讲，Mn 激活了 MTF-1/二价金属转运蛋白 1（DMT1）途径，增加了 Mn 在线粒体中的积累，并诱导了氧化应激。这反过来又通过 SIRT1 促进了 PPARγ 的去乙酰化，从而促进了脂质沉积。随后，PPARγ 通过转录激活脂肪酸转运蛋白、硬脂酰辅酶 A 去饱和酶 1 和脂联素 2 启动子介导 Mn 诱导的脂质积累。这些研究揭示了一个以前未知的机制，即 Mn 如何诱导肠道中的脂质沉积——氧化应激-SIRT1-PPARγ 途径。高膳食 Mn 摄入激活了 MTF-1/DMT1 和氧化应激途径。氧化应激介导的 PPARγ 在 K339 位点的去乙酰化有助于增加脂质积累。我们的研究结果提供了 Mn 与脂质代谢之间的直接联系——氧化应激-SIRT1-PPARγ 轴。
