Larter Claire Z, Yeh Matthew M, Cheng Jenny, Williams Jacqueline, Brown Sandie, dela Pena Aileen, Bell-Anderson Kim S, Farrell Geoffrey C
Australian National University Medical School at The Canberra Hospital, Canberra, Australian Capital Territory, Australia.
J Gastroenterol Hepatol. 2008 Feb;23(2):267-75. doi: 10.1111/j.1440-1746.2007.05157.x. Epub 2007 Sep 12.
Non-alcoholic fatty liver disease is the result of an imbalance in hepatic lipid partitioning that favors fatty acid synthesis and storage over fatty acid oxidation and triglyceride secretion. The progressive, inflammatory disorder of steatohepatitis can be prevented or reversed by correcting this lipid imbalance by activating peroxisome proliferator-activated receptor (PPAR) alpha, a transcription factor which regulates fatty acid oxidation. n-3 polyunsaturated fatty acids (PUFA), such as those found in fish oil (FO), are naturally occurring PPARalpha ligands which also suppress lipid synthesis.
We tested the role of dietary activation of PPARalpha by feeding mice a n-3 PUFA-enriched FO diet in the methionine and choline deficient (MCD) model of steatohepatitis. Results were compared with mice fed the corresponding diet supplemented with monounsaturated fatty acids as olive oil (OO).
As expected, FO feeding led to robust hepatic PPARalpha activation in control mice, and decreased expression of genes involved with fatty acid synthesis. Such lipolytic gene expression profile was also clearly evident in FO MCD-fed mice, and was associated with reduced hepatic lipid accumulation in comparison with mice fed OO MCD diet. FO feeding in control mice also caused marked hepatic accumulation of lipoperoxides compared with OO and chow-fed mice. This was further exacerbated in FO MCD-fed animals, which developed steatohepatitis characterized by mild steatosis and moderate inflammation in comparison with OO MCD-fed mice; such inflammatory recruitment was not related to NF-kappaB activation or enhanced cyclooxygenase-2 activity.
Feeding an n-3 PUFA-enriched diet activated PPARalpha and suppressed hepatic de novo lipogenesis, but failed to prevent development of steatohepatitis in the presence of methionine and choline deficiency. Instead, the very high levels of hepatic lipoperoxides may have abrogated the protection that would otherwise be conferred by PPARalpha activation, and could also be responsible for lipotoxic hepatocellular injury and inflammatory recruitment.
非酒精性脂肪性肝病是肝脏脂质分配失衡的结果，这种失衡使得脂肪酸合成和储存优先于脂肪酸氧化及甘油三酯分泌。通过激活过氧化物酶体增殖物激活受体（PPAR）α来纠正这种脂质失衡，可预防或逆转脂肪性肝炎这种进行性炎症性疾病，PPARα是一种调节脂肪酸氧化的转录因子。n-3多不饱和脂肪酸（PUFA），如鱼油（FO）中所含的此类脂肪酸，是天然存在的PPARα配体，也能抑制脂质合成。
在蛋氨酸和胆碱缺乏（MCD）的脂肪性肝炎模型中，我们通过给小鼠喂食富含n-3 PUFA的FO饮食来测试饮食激活PPARα的作用。将结果与喂食补充了单不饱和脂肪酸（如橄榄油，OO）的相应饮食的小鼠进行比较。
正如预期的那样，喂食FO导致对照小鼠肝脏PPARα强烈激活，并降低了与脂肪酸合成相关基因的表达。这种脂解基因表达谱在喂食FO的MCD小鼠中也很明显，与喂食OO MCD饮食的小鼠相比，其肝脏脂质积累减少。与喂食OO和普通饮食的小鼠相比，喂食FO的对照小鼠肝脏中也出现了明显的脂过氧化物积累。在喂食FO的MCD动物中，这种情况进一步恶化，与喂食OO MCD的小鼠相比，它们发展出了以轻度脂肪变性和中度炎症为特征的脂肪性肝炎；这种炎症细胞募集与NF-κB激活或环氧化酶-2活性增强无关。
喂食富含n-3 PUFA的饮食可激活PPARα并抑制肝脏从头脂肪生成，但在蛋氨酸和胆碱缺乏的情况下未能预防脂肪性肝炎的发生。相反，肝脏中极高水平的脂过氧化物可能消除了PPARα激活原本会提供的保护，也可能是脂毒性肝细胞损伤和炎症细胞募集的原因。
