Alterations in Lipid Metabolism Mediate Inflammation, Fibrosis, and Proliferation in a Mouse Model of Chronic Cholestatic Liver Injury

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 142; no. 1; pp. 140 - 151.e12
• Main Authors: Moustafa, Tarek, Fickert, Peter, Magnes, Christoph, Guelly, Christian, Thueringer, Andrea, Frank, Sasa, Kratky, Dagmar, Sattler, Wolfgang, Reicher, Helga, Sinner, Frank, Gumhold, Judith, Silbert, Dagmar, Fauler, Günter, Höfler, Gerald, Lass, Achim, Zechner, Rudolf, Trauner, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2012
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - deficiency; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Sub-Family B Member 4; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; Canalicular Phospholipid Flippase; Cell Proliferation; Cholestasis; 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; Gastroenterology and Hepatology; Gene Expression Profiling - methods; Gene Expression Regulation; Hepatitis - drug therapy; Hepatitis - genetics; Hepatitis - metabolism; Hepatitis - pathology; Hepatocellular Cancer; 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; PSC; Triglycerides - metabolism; Ursodeoxycholic Acid - analogs & derivatives; Ursodeoxycholic Acid - pharmacology; FFA; triglyceride; C/EBPα; LCA-CoA; high-density lipoprotein; HFD; fatty acid; double knockout; HDL; CCAAT/enhancer binding protein α; PPAR; Canalicular Phospholipid Flippase; 24- norursodeoxycholic acid; cholesterol; alkaline phosphatase; peroxisome proliferator-activated receptor; WT; PSC; bile acid; CH; DKO; DAG; AP; TG; free fatty acid; high-fat diet; long-chain acyl-CoA ester; Hepatocellular Cancer; FA; norUDCA; PL; phospholipid; wild-type; Cholestasis; diacylglycerol; BA
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.09.051

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- nor ursodeoxycholic acid ( nor UDCA) 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 nor UDCA. 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.