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Reduction of intestinal RIPK1 ameliorates HFD-induced metabolic disorders in female mice

ABSTRACT: Background Metabolic disorders including obesity, impaired glucose tolerance, dyslipidemia, and insulin resistance constitute a global public health problem that increases the risk of cardiovascular and type 2 diabetes. In modern society, a major cause of metabolic disorder is excessive nutrient intake from food. Therefore, as the main site of nutrient absorption, the intestine plays an important role in diet-induced metabolic disorders. However, it is still largely unknown on how the intestine participates in such a process. Results Here we show that ‘ileal jejunization’ is responsible for high-fat diet-induced metabolic disorders in female mice. Upon HFD-feeding, the transcriptional profile of the ileum was shifted towards that of jejunum which is characterized by increased expression of jejunal feature genes. Accordantly, the lipids uptake was increased in the ileum. Importantly, the HFD-induced ileal jejunization and metabolic disorders can be profoundly attenuated by intestinal-specific reduction of RIPK1. Interestingly, the HFD-induced increase in the expression of the jejunal feature genes in the ileum, and the effect of RIPK1 reduction were not observed in male mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE282889 | GEO | 2025/03/05

REPOSITORIES: GEO

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Project description:Background and Aims: Although the zinc finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. Methods: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. Results: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis demonstrated that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in mRNAs encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. Conclusion: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal versus ileal identity. Experiment Overall Design: Total RNA was harvested from the following sources and used to Affymetrix array analysis following manufacturer defined protocols: Experiment Overall Design: control jejunum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: mutant jejunum (Gata4loxP/-VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: control ileum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk). Experiment Overall Design: A total of nine Mouse Genome 430_2.0 arrays were hybridized for this study. Experiment Overall Design: Jejunum was defined as 10 cm from the pyloric sphincter, and ileum was defined as 1 cm from the cecum. The animals used to harvest control jejunum and ileum were independent of each other.

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Reduction of intestinal RIPK1 ameliorates HFD-induced metabolic disorders in female mice

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