Intestinal GATA4 deficiency protects from diet-induced hepatic steatosis.

Abstract

BACKGROUND & AIMS:

GATA4, a zinc finger domain transcription factor, is critical for jejunal identity. Mice with an intestine-specific GATA4 deficiency (GATA4iKO) are resistant to diet-induced obesity and insulin resistance. Although they have decreased intestinal lipid absorption, hepatic de novo lipogenesis is inhibited. Here, we investigated dietary lipid-dependent and independent effects on the development of steatosis and fibrosis in GATA4iKO mice.

METHODS:

GATA4iKO and control mice were fed a Western-type diet (WTD) or a methionine and choline-deficient diet (MCDD) for 20 and 3 weeks, respectively. Functional effects of GATA4iKO on diet-induced liver steatosis were investigated.

RESULTS:

WTD-but not MCDD-fed GATA4iKO mice showed lower hepatic concentrations of triglycerides, free fatty acids, and thiobarbituric acid reactive species and had reduced expression of lipogenic as well as fibrotic genes compared with controls. Reduced nuclear sterol regulatory element-binding protein-1c protein levels were accompanied by lower lipogenic gene expression. Oil red O and Sirius Red staining of liver sections confirmed the observed reduction in hepatic lipid accumulation and fibrosis. Immunohistochemical staining revealed an increased number of jejunal glucagon-like peptide 1 (GLP-1) positive cells in GATA4iKO mice. Consequently, we found enhanced phosphorylation of hepatic AMP-activated protein kinase and acetyl-CoA carboxylase alpha.

CONCLUSIONS:

Our results provide strong indications for a protective effect of intestinal GATA4 deficiency on the development of hepatic steatosis and fibrosis via GLP-1, thereby blocking hepatic de novo lipogenesis.

• Authors: Jay V Patankar, Sascha Obrowsky, Prakash Doddapattar, Gerald Hoefler, Michele Battle, Sanja Levak-Frank, Dagmar Kratky
• Journal: Journal of hepatology (J Hepatol) Vol. 57 Issue 5 Pg. 1061-8 (Nov 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22750465 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. All rights reserved.

Chemical References

• Fatty Acids, Nonesterified
• GATA4 Transcription Factor
• Gata4 protein, mouse
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Thiobarbituric Acid Reactive Substances
• Triglycerides
• Glucagon-Like Peptide 1
• Methionine
• Protein Kinases
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Choline Deficiency
• Diet (adverse effects)
• Disease Models, Animal
• Fatty Acids, Nonesterified (metabolism)
• Fatty Liver (chemically induced, metabolism, prevention & control)
• GATA4 Transcription Factor (deficiency, genetics, metabolism)
• Glucagon-Like Peptide 1 (metabolism)
• Jejunum (metabolism)
• Lipid Metabolism (physiology)
• Liver Cirrhosis (chemically induced, metabolism, prevention & control)
• Male
• Methionine (deficiency)
• Mice
• Mice, Knockout
• Protein Kinases (metabolism)
• Sterol Regulatory Element Binding Protein 1 (metabolism)
• Thiobarbituric Acid Reactive Substances (metabolism)
• Triglycerides (metabolism)