Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE155460 | GEO | 2021/05/10

REPOSITORIES: GEO

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Project description:High Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods, and its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the exact molecular mechanisms by which HFCS impacts hepatic metabolism are still unclear, especially in the context of obesity. In contrast, the vast majority of current studies in the field focus either on the detrimental role of fructose on NAFLD or compare the additive impact of fructose versus glucose in this process. Besides, studies elaborating on the role of fructose in NAFLD utilize molecular fructose, rather than HFCS, thus lacking simulation of human NAFLD in a more realistic way. Herein, by engaging combined omic approaches, we sought to characterize the additive impact of HFCS on NAFLD during obesity and recognize candidate pathways and molecules which could mediate the exaggeration of steatosis under these conditions. To achieve this goal, C57BL/6 male mice were fed a normal-fat (ND), a high-fat (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic and lipidomic analyses were conducted and utilized separately or in an integrated mode to identify HFCS-related molecular alterations of the hepatic metabolic landscape. Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed greater aggravation of hepatic steatosis. Importantly, the HFD-HFCS hepatic proteome was characterized by an upregulation of the enzymes implicated in de novo lipogenesis (DNL), while palmitic-acid containing diglycerides were significantly increased in the HFD-HFCS hepatic lipidome, as compared to the HFD group. Integrated omic analysis further suggested that TCA cycle overstimulation, is likely contributing towards the intensification of steatosis in the HFD-HFCS dietary theme. Overall, our results imply that HFCS may significantly contribute to NAFLD aggravation during obesity, with its fructose-rich properties being the main suspect.

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

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