Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.

Abstract

BACKGROUND & AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice.

• Authors: Tarek Moustafa, Peter Fickert, Christoph Magnes, Christian Guelly, Andrea Thueringer, Sasa Frank, Dagmar Kratky, Wolfgang Sattler, Helga Reicher, Frank Sinner, Judith Gumhold, Dagmar Silbert, Günter Fauler, Gerald Höfler, Achim Lass, Rudolf Zechner, Michael Trauner
• Journal: Gastroenterology (Gastroenterology) Vol. 142 Issue 1 Pg. 140-151.e12 (Jan 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22001865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Bile Acids and Salts
• Dietary Fats
• Fatty Acids
• Hypolipidemic Agents
• P-glycoprotein 2
• PPAR gamma
• Triglycerides
• Ursodeoxycholic Acid
• 24-norursodeoxycholic acid
• Fenofibrate

Topics

• ATP Binding Cassette Transporter, Subfamily B (deficiency, genetics)
• Animals
• Bile Acids and Salts (metabolism, pharmacology)
• Cell Proliferation
• Cholestasis, Intrahepatic (drug therapy, genetics, metabolism, pathology)
• Chronic Disease
• Dietary Fats (administration & dosage, metabolism)
• Disease Models, Animal
• Disease Progression
• Fatty Acids (metabolism)
• Female
• Fenofibrate (pharmacology)
• Gene Expression Profiling (methods)
• Gene Expression Regulation
• Hepatitis (drug therapy, genetics, metabolism, pathology)
• Hypolipidemic Agents (pharmacology)
• Lipid Metabolism (genetics)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (drug therapy, genetics, metabolism, pathology)
• Metabolomics
• Mice
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• PPAR gamma (deficiency, genetics)
• Pregnancy
• Prenatal Exposure Delayed Effects
• Triglycerides (metabolism)
• Ursodeoxycholic Acid (analogs & derivatives, pharmacology)