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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Moustafa, T; Fickert, P; Magnes, C; Guelly, C; Thueringer, A; Frank, S; Kratky, D; Sattler, W; Reicher, H; Sinner, F; Gumhold, J; Silbert, D; Fauler, G; Höfler, G; Lass, A; Zechner, R; Trauner, M.
Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.
Gastroenterology. 2012; 142(1):140-151
Doi: 10.1053/j.gastro.2011.09.051
Web of Science
PubMed
FullText
FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Moustafa Tarek
- Trauner Michael
- Co-Autor*innen der Med Uni Graz
- Fauler Günter
- Fickert Peter
- Frank Sasa
- Gülly Christian
- Hinteregger Helga
- Höfler Gerald
- Kratky Dagmar
- Sattler Wolfgang
- Silbert-Wagner Dagmar
- Sinner Frank Michael
- Sommer Judith
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- Abstract:
- The liver controls central processes of lipid and bile acid homeostasis. We aimed to investigate whether alterations in lipid metabolism contribute to the pathogenesis of chronic cholestatic liver disease in mice. We used microarray and metabolic profiling analyses to identify alterations in systemic and hepatic lipid metabolism in mice with disruption of the gene ATP-binding cassette sub-family B member 4 (Abcb4(-/-) mice), a model of inflammation-induced cholestatic liver injury, fibrosis, and cancer. Alterations in Abcb4(-/-) mice, compared with wild-type mice, included deregulation of genes that control lipid synthesis, storage, and oxidation; decreased serum levels of cholesterol and phospholipids; and reduced hepatic long-chain fatty acyl-CoAs (LCA-CoA). Feeding Abcb4(-/-) mice the side chain-modified bile acid 24-norursodeoxycholic acid (norUDCA) reversed their liver injury and fibrosis, increased serum levels of lipids, lowered phospholipase and triglyceride hydrolase activities, and restored hepatic LCA-CoA and triglyceride levels. Additional genetic and nutritional studies indicated that lipid metabolism contributed to chronic cholestatic liver injury; crossing peroxisome proliferator-activated receptor (PPAR)-α-deficient mice with Abcb4(-/-) mice (to create double knockouts) or placing Abcb4(-/-) mice on a high-fat diet protected against liver injury, with features similar to those involved in the response to norUDCA. Placing pregnant Abcb4(-/-) mice on high-fat diets prevented liver injury in their offspring. However, fenofibrate, an activator of PPARα, aggravated liver injury in Abcb4(-/-) mice. Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- ATP Binding Cassette Transporter, Subfamily B - deficiency
- ATP Binding Cassette Transporter, Subfamily B - genetics
- Animals -
- Bile Acids and Salts - metabolism
- Bile Acids and Salts - pharmacology
- Cell Proliferation -
- Cholestasis, Intrahepatic - drug therapy
- Cholestasis, Intrahepatic - genetics
- Cholestasis, Intrahepatic - metabolism
- Cholestasis, Intrahepatic - pathology
- Chronic Disease -
- Dietary Fats - administration & dosage
- Dietary Fats - metabolism
- Disease Models, Animal -
- Disease Progression -
- Fatty Acids - metabolism
- Female -
- Fenofibrate - pharmacology
- Gene Expression Profiling - methods
- Gene Expression Regulation -
- Hepatitis - drug therapy
- Hepatitis - genetics
- Hepatitis - metabolism
- Hepatitis - pathology
- Hypolipidemic Agents - pharmacology
- Lipid Metabolism - genetics
- Liver - drug effects
- Liver - metabolism
- Liver - pathology
- Liver Cirrhosis - drug therapy
- Liver Cirrhosis - genetics
- Liver Cirrhosis - metabolism
- Liver Cirrhosis - pathology
- Metabolomics -
- Mice -
- Mice, Knockout -
- Oligonucleotide Array Sequence Analysis -
- PPAR gamma - deficiency
- PPAR gamma - genetics
- Pregnancy -
- Prenatal Exposure Delayed Effects -
- Triglycerides - metabolism
- Ursodeoxycholic Acid - analogs & derivatives
- Ursodeoxycholic Acid - pharmacology
- Find related publications in this database (Keywords)
- Cholestasis
- Canalicular Phospholipid Flippase
- Hepatocellular Cancer
- PSC