Intestinal GATA4 deficiency protects from diet-induced hepatic steatosis
| Autor: | Prakash Doddapattar, Sascha Obrowsky, Gerald Hoefler, Dagmar Kratky, Sanja Levak-Frank, Michele A. Battle, Jay V. Patankar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Liver Cirrhosis
Male Fatty Acids Nonesterified chemistry.chemical_compound Mice 0302 clinical medicine Methionine AMP-activated protein kinase AMP-Activated Protein Kinase Kinases AST aspartate transaminase Glucagon-Like Peptide 1 TBARS thiobarbituric acid reactive substances FFA free fatty acids De novo lipogenesis 2. Zero hunger p phosphorylated Mice Knockout 0303 health sciences biology LDH lactate dehydrogenase Intestinal lipid absorption Fatty liver α-SMA alpha-smooth muscle actin GLP-1 glucagon-like peptide-1 TG triglycerides 3. Good health WTD Western-type diet Choline Deficiency SREBP-1c sterol regulatory element-binding protein-1c Jejunum Lipogenesis 030211 gastroenterology & hepatology Sterol Regulatory Element Binding Protein 1 ACC acetyl-CoA carboxylase alpha HSC hepatic stellate cells Research Article endocrine system medicine.medical_specialty NAFLD non-alcoholic fatty liver disease DNL de novo lipogenesis Ileal interposition surgery Thiobarbituric Acid Reactive Substances 03 medical and health sciences GATA4iKO intestine-specific GATA4 deficiency GATA4 Internal medicine ALT alanine aminotransferase medicine Oil Red O Animals Sirius Red Triglycerides 030304 developmental biology p38 p38 mitogen-activated protein kinase Hepatology IIS ileal interposition surgery Pparg peroxisome proliferator-activated receptor gamma medicine.disease Lipid Metabolism Diet GATA4 Transcription Factor Fatty Liver AMPK AMP-activated protein kinase Disease Models Animal Endocrinology chemistry Hepatic stellate cell biology.protein MCDD methionine and choline-deficient diet Steatosis GLP-1 Protein Kinases Non-alcoholic fatty liver disease |
| Zdroj: | Journal of Hepatology |
| ISSN: | 1600-0641 0168-8278 |
| Popis: | Background & Aims GATA4, a zinc finger domain transcription factor, is critical for jejunal identity. Mice with an intestine-specific GATA4 deficiency ( GATA4 iKO) 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 GATA4 iKO mice. Methods GATA4 iKO and control mice were fed a Western-type diet (WTD) or a methionine and choline-deficient diet (MCDD) for 20 and 3weeks, respectively. Functional effects of GATA4 iKO on diet-induced liver steatosis were investigated. Results WTD-but not MCDD-fed GATA4 iKO 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 GATA4 iKO 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect