title: Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.
abstract: OBJECTIVE
  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: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors: Tarek
authors: T
authors: Moustafa
authors: Peter
authors: P
authors: Fickert
authors: Christoph
authors: C
authors: Magnes
authors: Christian
authors: C
authors: Guelly
authors: Andrea
authors: A
authors: Thueringer
authors: Sasa
authors: S
authors: Frank
authors: Dagmar
authors: D
authors: Kratky
authors: Wolfgang
authors: W
authors: Sattler
authors: Helga
authors: H
authors: Reicher
authors: Frank
authors: F
authors: Sinner
authors: Judith
authors: J
authors: Gumhold
authors: Dagmar
authors: D
authors: Silbert
authors: Günter
authors: G
authors: Fauler
authors: Gerald
authors: G
authors: Höfler
authors: Achim
authors: A
authors: Lass
authors: Rudolf
authors: R
authors: Zechner
authors: Michael
authors: M
authors: Trauner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014280:Triglycerides / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D004041:Dietary Fats; D005227:Fatty Acids; D011345:Fenofibrate; D000960:Hypolipidemic Agents; D047495:PPAR gamma; D014280:Triglycerides; D014580:Ursodeoxycholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C081331:24-norursodeoxycholic acid