Li Heng-Hong, Tyburski John B, Wang Yi-Wen, Strawn Steve, Moon Bo-Hyun, Kallakury Bhaskar V S, Gonzalez Frank J, Fornace Albert J
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia.
Alcohol Clin Exp Res. 2014 Jun;38(6):1520-31. doi: 10.1111/acer.12424. Epub 2014 Apr 28.
Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor α (PPARα)-null mice developed more pronounced hepatic changes than wild-type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of alcoholic liver disease (ALD) in Ppara-null model and in humans, and the fact that PPARα expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD.
In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARα activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in WT mice.
The results showed that in the presence of PPARα, 3 major metabolic pathways in mitochondria, namely the fatty acid β-oxidation, the tricarboxylic acid cycle, and the electron transfer chain, were induced in response to a 2-month alcohol feeding, while these responses were greatly reduced in the absence of PPARα. In line with the transcriptional modulations of these metabolic pathways, a progressive accumulation of triglycerides, a robust increase in hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes were observed exclusively in alcohol-fed Ppara-null mice.
These observations indicate that PPARα plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment for ALD.
长期饮酒会影响肝功能并导致肝脏病理变化。研究表明，过氧化物酶体增殖物激活受体α（PPARα）基因敲除小鼠在长期摄入含4%酒精的饮食后，肝脏变化比野生型（WT）小鼠更为明显。PPARα基因敲除模型中酒精性肝病（ALD）的组织病理学与人类的显著相似，以及人类肝脏中PPARα的表达和活性不到WT小鼠肝脏的十分之一，这使得PPARα基因敲除成为研究ALD的良好模型。
在本研究中，使用PPARα基因敲除模型来阐明长期饮酒过程中PPARα活性的动态调节。采用肝脏转录组学和代谢组学分析来检测与病理变化相关的基因表达和代谢物的改变。将PPARα基因敲除小鼠中酒精摄入引发的基因表达和代谢物变化与WT小鼠进行比较。
结果显示，在有PPARα的情况下，给予2个月酒精喂养后，线粒体中的3条主要代谢途径，即脂肪酸β氧化、三羧酸循环和电子传递链被诱导，而在没有PPARα的情况下，这些反应大大减弱。与这些代谢途径的转录调节一致，仅在酒精喂养的PPARα基因敲除小鼠中观察到甘油三酯的逐渐积累、肝脏胆酸及其衍生物的显著增加以及纤维生成基因的强烈诱导。
这些观察结果表明，PPARα通过适应性转录激活对长期酒精摄入起到保护作用，增强线粒体功能，并表明激活这种核受体可能对ALD的治疗具有治疗价值。
