Knebel Birgit, Göddeke Simon, Hartwig Sonja, Hörbelt Tina, Fahlbusch Pia, Al-Hasani Hadi, Jacob Sylvia, Koellmer Cornelia, Nitzgen Ulrike, Schiller Martina, Lehr Stefan, Kotzka Jorg
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany.
German Center of Diabetes Research Partner, Duesseldorf, Germany.
Proteomics Clin Appl. 2018 Jan;12(1). doi: 10.1002/prca.201700028. Epub 2017 Dec 11.
Metabolic syndrome (MetS) consists of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia, and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation on MetS is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e., mitochondria and peroxisomes.
The New Zealand Obese (NZO) mouse model exhibits a polygenic syndrome of obesity, insulin resistance, triglyceridemia, and hypercholesterolemia that resembles human metabolic syndrome. We applied a multi-omics approach combining lipidomics with liver transcriptomics and top-down MS based organelle proteomics (2D-DIGE) of highly enriched mitochondria and peroxisomes in male mice, to investigate molecular mechanisms related to the impact of lipid metabolism in the pathophysiology of the metabolic syndrome.
Proteome analyses of liver organelles indicate differences in fatty acid and cholesterol metabolism, mainly influenced by PG-C1α/PPARα and other nuclear receptor mediated pathways. These results are in accordance with altered serum lipid profiles and elevated organelle functionality. These data emphasize that metabolic syndrome is accompanied with increased mitochondria and peroxisomal activity to cope with dyslipidemia and hypercholesterinemia driven hepatic lipid overflow in developing a fatty liver.
代谢综合征（MetS）由五个风险因素组成：血压升高、空腹血糖升高、内脏肥胖、血脂异常和高胆固醇血症。脂质代谢的生理影响，如内脏肥胖和肝脏脂质积累对代谢综合征的影响仍存在争议。脂质代谢紊乱的一个主要原因可能是控制能量稳态的细胞器功能障碍，即线粒体和过氧化物酶体。
新西兰肥胖（NZO）小鼠模型表现出一种多基因综合征，包括肥胖、胰岛素抵抗、高甘油三酯血症和高胆固醇血症，类似于人类代谢综合征。我们采用了一种多组学方法，将脂质组学与肝脏转录组学以及基于自上而下质谱的雄性小鼠高度富集的线粒体和过氧化物酶体的细胞器蛋白质组学（二维差异凝胶电泳）相结合，以研究脂质代谢在代谢综合征病理生理学中的影响相关的分子机制。
肝脏细胞器的蛋白质组分析表明脂肪酸和胆固醇代谢存在差异，主要受PG-C1α/PPARα和其他核受体介导的途径影响。这些结果与血清脂质谱的改变和细胞器功能的升高一致。这些数据强调，代谢综合征伴随着线粒体和过氧化物酶体活性增加，以应对血脂异常和高胆固醇血症驱动的肝脏脂质溢出，从而发展为脂肪肝。
