Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Patankar, JV.
Intestinal GATA-4 mediates regulation of lipid homeostasis in vivo
[ Dissertation ] Medical University of Graz; 2011. pp.86.
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- Autor*innen der Med Uni Graz:
- Patankar Jay Vasant
- Betreuer*innen:
- Heinemann Akos
- Levak Sanja
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- Abstract:
- Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA-4, a zinc finger domain transcription factor, is critical for jejunal identity and intestinal GATA-4 deficiency leads to a jejuno-ileal transition. Although intestinal GATA-4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine specific GATA-4 knockout mice (GATA4iKO) to dissect the contribution of GATA-4 on obesity development. We challenged adult GATA4iKO and control littermates with a Western-type diet (WTD) for 20 weeks. Our findings show that WTD-fed GATA4iKO mice are resistant to diet induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater GLP-1 release on normal chow and even after long term challenge with WTD and remained glucose sensitive. Given a higher GLP-1 release we also found a reduced gastric emptying in these mice. On the other hand GATA4iKO mice showed attenuation in Gip release upon fat load leading to a suppression of lipid absorption via chylomicrons. These mice also showed higher glucose stimulated insulin release upon oral fat load which contributes to their reduced absorption of dietary fat. GATA4iKO mice also showed lower accumulation of lipids in the liver and exhibited a healthier gene expression profile compared to controls for lipogenic and steatotic potential. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia, obesity and non-alcoholic fatty liver disease. In addition, the increase in GLP-1 release in GATA4iKO mice shows that these mice have an improved ability to counter insulin resistance after feeding a WTD.