Nonalcoholic fatty liver disease (NAFLD) and its evolution to inflammatory steatohepatitis (NASH) are the most common causes of chronic liver damage and transplantation that are reaching epidemic proportions due to the upraising incidence of metabolic syndrome, obesity, and diabetes. Currently, there is no approved treatment for NASH. The mitochondrial citrate carrier, Slc25a1, has been proposed to play an important role in lipid metabolism, suggesting a potential role for this protein in the pathogenesis of this disease. Here, we show that Slc25a1 inhibition with a specific inhibitor compound, CTPI-2, halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, while starkly mitigating obesity induced by a high-fat diet. These effects are differentially recapitulated by a global ablation of one copy of the Slc25a1 gene or by a liver-targeted Slc25a1 knockout, which unravel dose-dependent and tissue-specific functions of this protein. Mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts signaling from peroxisome proliferator-activated receptor gamma, a key regulator of glucose and lipid metabolism, and inhibits the expression of gluconeogenic genes. The combination of these activities leads not only to inhibition of lipid anabolic processes, but also to a normalization of hyperglycemia and glucose intolerance as well. In summary, our data show for the first time that Slc25a1 serves as an important player in the pathogenesis of fatty liver disease and thus, provides a potentially exploitable and novel therapeutic target.

中文翻译：

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在 NAFLD/NASH 的临床前模型中，抑制线粒体柠檬酸盐载体 Slc25a1 可逆转脂肪变性、葡萄糖耐受不良和炎症。

非酒精性脂肪性肝病 (NAFLD) 及其向炎症性脂肪性肝炎 (NASH) 的演变是慢性肝损伤和移植的最常见原因，由于代谢综合征、肥胖和糖尿病的发病率上升，这些疾病已达到流行程度。目前，没有批准的 NASH 治疗方法。已提出线粒体柠檬酸盐载体 Slc25a1 在脂质代谢中发挥重要作用，表明该蛋白质在该疾病的发病机制中具有潜在作用。在这里，我们展示了用一种特定的抑制剂化合物 CTPI-2 抑制 Slc25a1，可以阻止 NASH 的显着改变，逆转脂肪变性，防止演变为脂肪性肝炎，减少肝脏和脂肪组织中的炎性巨噬细胞浸润，同时显着减轻由高浓度引起的肥胖。 - 脂肪饮食。这些影响通过 Slc25a1 基因的一个拷贝的整体消融或肝脏靶向的 Slc25a1 敲除来不同地概括，这揭示了该蛋白质的剂量依赖性和组织特异性功能。从机制上讲，通过柠檬酸盐依赖性活性，Slc25a1 抑制重新连接脂肪生成程序，减弱来自过氧化物酶体增殖物激活受体 γ（葡萄糖和脂质代谢的关键调节剂）的信号，并抑制糖异生基因的表达。这些活动的组合不仅导致脂质合成代谢过程的抑制，而且导致高血糖和葡萄糖耐受不良的正常化。总之，我们的数据首次表明 Slc25a1 在脂肪肝发病机制中扮演着重要角色，因此，