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

被引：126

作者：

Moustafa, Tarek ^{[1
,2
]}

Fickert, Peter ^{[2
]}

Magnes, Christoph ^{[8
]}

Guelly, Christian ^{[3
]}

Thueringer, Andrea ^{[4
]}

Frank, Sasa ^{[5
]}

Kratky, Dagmar ^{[5
]}

Sattler, Wolfgang ^{[5
]}

Reicher, Helga ^{[5
]}

Sinner, Frank ^{[8
]}

Gumhold, Judith ^{[2
]}

Silbert, Dagmar ^{[2
]}

Fauler, Guenter ^{[6
,7
]}

Hoefler, Gerald ^{[4
]}

Lass, Achim

Zechner, Rudolf

Trauner, Michael ^{[1
,2
]}

机构：

[1] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Hans Popper Lab Mol Hepatol, A-1090 Vienna, Austria

[2] Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, Lab Expt & Mol Hepatol, Graz, Austria

[3] Med Univ Graz, Med Res Ctr, Graz, Austria

[4] Med Univ Graz, Inst Pathol, Graz, Austria

[5] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[6] Med Univ Graz, Inst Clin Med, Graz, Austria

[7] Med Univ Graz, Chem Lab Diagnost, Graz, Austria

[8] Joanneum Res, HEALTH Inst Biomed & Hlth Sci, Graz, Austria

来源：

GASTROENTEROLOGY | 2012年 / 142卷 / 01期

基金：

奥地利科学基金会;

关键词：

Cholestasis; Canalicular Phospholipid Flippase; Hepatocellular Cancer; PSC; GLYCOPROTEIN-DEFICIENT MICE; ENDOTHELIAL LIPASE; NONALCOHOLIC STEATOHEPATITIS; SCLEROSING CHOLANGITIS; STEROL LOSS; IN-VIVO; GENE; ACID; PATHOGENESIS; DISEASE;

D O I：

10.1053/j.gastro.2011.09.051

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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)-alpha-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 PPAR alpha, aggravated liver injury in Abcb4(-/-) mice. CONCLUSIONS: Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice.

引用

页码：140 / U308

页数：24

共 28 条

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