Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and suggest drug candidates for both lean MASLD and support of urea cycle function in CD. To determine whether deletion of NADH shuttle systems and/or provision of glycerol resulted in a ChREBP transcriptional program, we harvested livers from 40 mice representing water and glycerol-exposed males of the four genotypes, prepared cDNA and performed bulk paired-end 150 base-pair RNA sequencing (RNAseq)61 using an Illumina NovaSeq X Plus sequencer at >20 million paired reads per sample.

Citrin缺乏症（Citrin Deficiency，CD）由SLC25A13功能失活引发，该基因编码的线粒体膜蛋白是肝细胞中将胞质NADH的电子转运至线粒体基质所必需的因子。CD患者对甜食存在厌恶倾向。本研究发现，SLC25A13缺失会导致甘油-3-磷酸（glycerol-3-phosphate，G3P）蓄积，后者可激活碳水化合物反应元件结合蛋白（carbohydrate response element binding protein，ChREBP），介导FGF21的转录；FGF21可作用于大脑，抑制甜食与酒精摄入，同时还可转录调控从头脂肪生成的关键基因。小鼠与人类样本数据证实，G3P-ChREBP通路是兰德尔循环（Randle Cycle）的全新机制组分，该通路参与代谢功能障碍相关性脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）的发病进程，并构成了肝脏向大脑传递代谢状态的信号系统之一，进而改变机体的食物与酒精选择偏好。本研究数据为解析多种生理病理条件下FGF21的诱导机制提供了理论框架，为开发FGF21诱导类药物提供了新思路，同时也为非肥胖型MASLD的治疗以及改善CD患者的尿素循环功能提供了潜在候选药物。为明确NADH穿梭系统缺失及/或甘油补充是否会引发ChREBP介导的转录程序，本研究采集了40只小鼠的肝脏组织：这些小鼠均为四种基因型的雄性个体，分别经水溶液或甘油处理；随后提取总RNA并制备cDNA，使用Illumina NovaSeq X Plus测序仪开展批量双端150碱基对RNA测序（RNAseq）61，单样本双端测序读段数均超过2000万条。