MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

MYC 是一种具有广泛生物学功能的转录因子，特别是在控制细胞增殖方面。在这里，我们表明肠道 MYC 调节全身代谢。我们发现 MYC 表达在肥胖个体的回肠活检中增加，并且与体重指数呈正相关。小鼠 MYC 的肠道特异性减少可改善高脂肪饮食引起的肥胖、胰岛素抵抗、肝脂肪变性和脂肪性肝炎。从机制上讲，肠道中 MYC 表达减少会促进胰高血糖素样肽-1 (GLP-1) 的产生和分泌。此外，我们确定了Cers4，编码神经酰胺合成酶 4，催化神经酰胺从头合成，作为 MYC 靶基因。最后，我们表明施用 MYC 抑制剂 10058-F4 对高脂肪饮食诱导的代谢紊乱具有有益作用，并伴随着 GLP-1 增加和血清中神经酰胺水平降低。本研究将肠道 MYC 定位为治疗代谢性疾病（包括非酒精性脂肪肝和非酒精性脂肪性肝炎）的推定药物靶点。