Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Gastroenterology. 2012 Jan;142(1):140-151.e12. doi: 10.1053/j.gastro.2011.09.051. Epub 2011 Oct 14.
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.
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.
肝脏控制着脂质和胆汁酸稳态的核心过程。我们旨在研究脂质代谢的改变是否会导致小鼠慢性胆汁淤积性肝病的发病机制。
我们使用微阵列和代谢谱分析来鉴定基因 ATP 结合盒亚家族 B 成员 4（Abcb4(-/-) 小鼠）敲除小鼠，即炎症诱导的胆汁淤积性肝损伤、纤维化和癌症模型中，全身和肝脂质代谢的改变。
与野生型小鼠相比，Abcb4(-/-) 小鼠的改变包括控制脂质合成、储存和氧化的基因失调；胆固醇和磷脂血清水平降低；以及肝长链脂肪酸辅酶 A（LCA-CoA）减少。用侧链修饰的胆汁酸 24-去氧胆酸（norUDCA）喂养 Abcb4(-/-) 小鼠可逆转其肝损伤和纤维化，增加脂质血清水平，降低磷脂酶和甘油三酯水解酶活性，并恢复肝 LCA-CoA 和甘油三酯水平。进一步的遗传和营养研究表明，脂质代谢有助于慢性胆汁淤积性肝损伤；将过氧化物酶体增殖物激活受体（PPAR）-α 缺陷型小鼠与 Abcb4(-/-) 小鼠杂交（创建双敲除）或将 Abcb4(-/-) 小鼠置于高脂肪饮食中可预防肝损伤，其特征类似于 norUDCA 反应涉及的特征。将怀孕的 Abcb4(-/-) 小鼠置于高脂肪饮食中可防止其后代的肝损伤。然而，激活 PPARα 的非诺贝特加重了 Abcb4(-/-) 小鼠的肝损伤。
脂质代谢的改变有助于小鼠胆汁淤积性肝病的发病机制和进展。
