Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, People's Republic of China.
Am J Physiol Cell Physiol. 2024 Sep 1;327(3):C737-C749. doi: 10.1152/ajpcell.00194.2024. Epub 2024 Jul 29.
The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish () and Nile tilapia () to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD. The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.
线粒体柠檬酸穿梭系统依赖溶质载体家族 25 成员 1（SLC25A1），在将柠檬酸从线粒体转运到细胞质中发挥关键作用。该穿梭系统支持糖酵解、脂质生物合成和蛋白质乙酰化。先前的研究主要集中在病理模型中的 SLC25A1，特别是高脂肪饮食（HFD）诱导的肥胖。然而，SLC25A1 抑制在 HFD 下对营养代谢的影响尚不清楚。为了解决这一差距，我们使用斑马鱼（）和尼罗罗非鱼（）来评估抑制 Slc25a1 的效果。在斑马鱼中，我们用 SLC25A1 特异性抑制剂（CTPI-2）处理 4 周，而尼罗罗非鱼则接受腹腔内注射 dsRNA 以敲低 slc25a1b 7 天。线粒体柠檬酸穿梭的抑制有效地保护斑马鱼免受 HFD 诱导的肥胖、肝脂肪变性和胰岛素抵抗。值得注意的是，葡萄糖耐量不受影响。抑制 Slc25a1 改变了肝蛋白乙酰化模式，细胞质乙酰化减少，线粒体乙酰化增加。在 HFD 条件下，Slc25a1 抑制通过去乙酰化肉碱棕榈酰转移酶 1a（Cpt1a）促进脂肪酸氧化并减少肝三酰基甘油（TAG）积累。此外，Slc25a1 抑制触发 Pdhe1α 的乙酰化诱导失活，导致葡萄糖氧化分解代谢减少。这伴随着斑马鱼肝中葡萄糖摄取和储存的增加。此外，HFD 条件下 Slc25a1 抑制激活 SIRT1/PGC1α 途径，促进线粒体增殖并增强氧化磷酸化以产生能量。我们的研究结果为非组蛋白蛋白乙酰化通过线粒体柠檬酸穿梭在 HFD 引起的肝脂质沉积和高血糖发展中的作用提供了新的见解。线粒体柠檬酸穿梭是维持代谢稳态的关键生理过程。在本研究中，我们发现通过重塑肝蛋白乙酰化修饰，抑制线粒体柠檬酸穿梭（Slc25a1）可以减轻高脂肪饮食（HFD）引起的代谢综合征。简而言之，Slc25a1 抑制通过去乙酰化 Cpt1a 减少肝三酰基甘油沉积，通过乙酰化 Pdhe1α 减少葡萄糖氧化分解代谢。我们的研究为饮食诱导的代谢综合征的治疗提供了新的见解。
