Knebel Birgit, Hartwig Sonja, Haas Jutta, Lehr Stefan, Goeddeke Simon, Susanto Franciscus, Bohne Lothar, Jacob Sylvia, Koellmer Cornelia, Nitzgen Ulrike, Müller-Wieland Dirk, Kotzka Jorg
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University Duesseldorf, Aufm Hennekamp 65, Duesseldorf 40225, Germany.
Institute for Diabetes Research, Department of General Internal Medicine, Asklepios Clinic St. Georg, Medical Faculty of Semmelweis University, Asklepios Campus Hamburg, Lohmuehlen Str 5, Hamburg 20099, Germany.
Biochim Biophys Acta. 2015 Jul;1851(7):965-76. doi: 10.1016/j.bbalip.2015.03.003. Epub 2015 Mar 17.
Major causes of lipid accumulation in liver are increased import or synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelles controlling energy homeostasis, i.e., mitochondria. Peroxisomes also appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non-alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes alongside mitochondria in excessive hepatic lipid accumulation, we used leptin-resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia-induced diabetes with obesity and NAFLD. Proteome and gene expression analyses along with lipid analyses in the liver revealed differential expression of genes related to lipid metabolism and β-oxidation, whereas genes for peroxisomal proteins were predominantly regulated.
Our investigations show that in fatty liver disease in combination with obesity and diabetes, the hepatocyte-protecting organelle peroxisome is altered. Hence, peroxisomes might indicate a stage of pre-NAFLD, play a role in the early development of NAFLD and appear to be a potential target for treatment and prevention of NAFLD.
肝脏脂质蓄积的主要原因是脂肪酸的输入增加或合成增加，或脂肪酸分解代谢减少。后者是由控制能量稳态的细胞器即线粒体功能障碍引起的。过氧化物酶体似乎也是肝细胞脂质代谢中的一个重要细胞器，但对其在非酒精性脂肪性肝病（NAFLD）发生发展中的作用知之甚少。为了研究过氧化物酶体与线粒体在肝脏脂质过度蓄积中的作用，我们使用了C57BLKS背景的瘦素抵抗db/db小鼠，这是一种因摄食过多导致肥胖和NAFLD的糖尿病小鼠模型。肝脏中的蛋白质组和基因表达分析以及脂质分析揭示了与脂质代谢和β氧化相关基因的差异表达，而过氧化物酶体蛋白的基因则受到主要调控。
我们的研究表明，在伴有肥胖和糖尿病的脂肪性肝病中，具有肝细胞保护作用的细胞器过氧化物酶体发生了改变。因此，过氧化物酶体可能预示着NAFLD前期阶段，在NAFLD的早期发展中起作用，并且似乎是NAFLD治疗和预防的一个潜在靶点。
