Next Generation Sequencing Analysis of Mycfl/fl and MycΔIE, ERT2 intestinal transcriptomes

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in developed countries, with extremely limited therapeutic options. MYC is a highly pleiotropic transcription factor with broad biological functions. However, the effect of intestinal MYC on metabolic diseases has not been studied. Here, an unexpected role for intestinal MYC in NAFLD was uncovered. MYC was increased in ileum biopsies from obese people and positively correlated with body-mass index. Intestine-specific reduction of MYC in mice improved high-fat diet (HFD) -induced obesity and hepatic steatosis. Mechanistically, reduced expression of MYC in the intestine promoted glucagon-like peptide-1 (GLP-1) production and secretion via upregulating carbohydrate-responsive element binding protein (ChREBP) and solute carrier family 2, member 2 (GLUT2)/solute carrier family 5, member 1 (SGLT1), respectively. Furthermore, 10058-F4, a MYC inhibitor, had therapeutic effects on HFD-induced metabolic disorders, accompanied by increased GLP-1 and reduced ceramides in the serum. This study highlights intestinal MYC as a putative drug target against NAFLD. Bulk RNA-seq of RNA isolated from the intestine of HFD-fed Mycfl/fl and MycΔIE, ERT2 mice.