School of Human Nutrition, Faculty of Agricultural and Environmental Science, McGill University, Ste Anne de Bellevue, Québec, Canada.
Goodman Cancer Institute, McGill University, Qc, H3A 1A3, Montréal, Québec, Canada; Department of Medicine, McGill University, Qc, H3A 1A3, Montréal, Québec, Canada.
Free Radic Biol Med. 2024 Nov 1;224:660-677. doi: 10.1016/j.freeradbiomed.2024.09.016. Epub 2024 Sep 14.
In the present study, we investigated the consequences of deleting the glutaredoxin-2 gene (Glrx2) on the development of non-alcoholic fatty liver disease (NAFLD) in male and female C57BL6N mice fed a control (CD) or high-fat diet (HFD). We report that the HFD induced a significant increase in body mass in the wild-type (Wt) and Glrx2 male, but not female, mice, which was associated with the hypertrophying of the abdominal fat. Interestingly, while the Wt male mice fed the HFD developed NAFLD, the deletion of the Glrx2 gene mitigated vesicle formation, intrahepatic lipid accumulation, and fibrosis in the males. The protective effect associated with ablating the Glrx2 gene in male mice was due to enhancement of mitochondrial redox buffering capacity. Specifically, liver mitochondria from male Glrx2 fed a CD or HFD produced significantly less hydrogen peroxide (mtHO), had lower malondialdehyde levels, greater activities for glutathione peroxidase and thioredoxin reductase, and less protein glutathione mixed disulfides (PSSG) when compared to the Wt male mice fed the HFD. These effects correlated with the S-glutathionylation of α-ketoglutarate dehydrogenase (KGDH), a potent mtHO source and key redox sensor in hepatic mitochondria. In comparison to the male mice, both Wt and Glrx2 female mice displayed almost complete resistance to HFD-induced body mass increases and the development of NAFLD, which was attributed to the superior redox buffering capacity of the liver mitochondria. Together, our findings show that modulation of mitochondrial S-glutathionylation signaling through Glrx2 augments resistance of male mice towards the development of NAFLD through preservation of mitochondrial redox buffering capacity. Additionally, our findings demonstrate the sex dimorphisms associated with the manifestation of NAFLD is related to the superior redox buffering capacity and modulation of the S-glutathionylome in hepatic mitochondria from female mice.
在本研究中，我们研究了敲除谷氧还蛋白-2 基因（Glrx2）对雄性和雌性 C57BL6N 小鼠在给予对照（CD）或高脂肪饮食（HFD）时非酒精性脂肪性肝病（NAFLD）发展的影响。我们报告称，HFD 显著增加了野生型（Wt）和 Glrx2 雄性小鼠的体重，但不影响雌性小鼠，这与腹部脂肪肥大有关。有趣的是，虽然 Wt 雄性小鼠在给予 HFD 后发展为 NAFLD，但 Glrx2 基因的缺失减轻了雄性小鼠的囊泡形成、肝内脂质积累和纤维化。与在雄性小鼠中敲除 Glrx2 基因相关的保护作用是由于增强了线粒体氧化还原缓冲能力。具体而言，与给予 HFD 的 Wt 雄性小鼠相比，Glrx2 喂养的雄性小鼠的肝线粒体产生的过氧化氢（mtHO）显著减少，丙二醛水平降低，谷胱甘肽过氧化物酶和硫氧还蛋白还原酶活性更高，蛋白质谷胱甘肽混合二硫化物（PSSG）水平更低，当与给予 HFD 的 Wt 雄性小鼠相比时。这些影响与α-酮戊二酸脱氢酶（KGDH）的 S-谷胱甘肽化相关，KGDH 是肝线粒体中 mtHO 的主要来源和关键氧化还原传感器。与雄性小鼠相比，Wt 和 Glrx2 雌性小鼠对 HFD 诱导的体重增加和 NAFLD 的发展几乎完全具有抗性，这归因于肝线粒体的优越氧化还原缓冲能力。总之，我们的研究结果表明，通过 Glrx2 调节线粒体 S-谷胱甘肽化信号增强了雄性小鼠对 NAFLD 发展的抵抗力，这是通过维持线粒体氧化还原缓冲能力实现的。此外，我们的研究结果表明，与 NAFLD 表现相关的性别二态性与雌性小鼠肝线粒体中优越的氧化还原缓冲能力和 S-谷胱甘肽组的调节有关。
