PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation
PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation
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DOI：
10.1016/j.ajpath.2015.01.018
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发表时间：
2015-05-01
影响因子：
6
通讯作者：
Reddy, Janardan K.
中科院分区：
文献类型：
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作者：
Gao, Qian;Jia, Yuzhi;Reddy, Janardan K.
肥胖会增加患代谢综合征和密切相关的非酒精性脂肪肝疾病（包括肝癌）的风险。饱腹感激素瘦素缺乏（ob/ob）小鼠被认为是营养性肥胖的典型，会发生肝脂肪变性，但不太容易发生肝肿瘤。 ob/ob小鼠肝脏中过氧化物酶体增殖物激活受体α（PPARα）的持续激活会增加脂肪酸氧化（FAO），这有助于减轻肥胖，但会增加患肝癌的风险。为了进一步评估PPARα调节的肝脏FAO和能量燃烧在脂肪肝疾病进展中的作用，我们培育了PPARα缺陷ob/ob（PPARα(Delta)ob/ob）小鼠。与 ob/ob 同窝小鼠相比，这些小鼠变得更加肥胖，白色和棕色脂肪组织含量增加，并且肝脏脂肪变性严重。禁食的 PPAR α(Delta)ob/ob 小鼠的肝脏脂肪变性变得更加严重，因为它们无法上调FAO系统。 PPAR α(Delta)ob/ob 小鼠也不对 PPAR α 激动剂 Wy-14,643 的过氧化物酶体增殖和促有丝分裂作用产生反应。尽管 PPAR α(Delta)ob/ob 小鼠严重肥胖，但即使维持含有 Wy-14,643 的饮食，肝脏肿瘤发病率也没有显着增加。我们得出的结论是，肥胖ob/ob小鼠脂肪肝中与PPARα激活相关的FAO持续增加会增加肝癌风险，而ob/ob小鼠中PPARα的缺失会加剧肥胖和肝脂肪变性。然而，由于FAO减少和能量消耗，它不会导致肝脏肿瘤的发展。
Obesity poses an increased risk of developing metabolic syndrome and closely associated nonalcoholic fatty liver disease, including liver cancer. Satiety hormone leptin-deficient (ob/ob) mice, considered paradigmatic of nutritional obesity, develop hepatic steatosis but are less prone to developing liver tumors. Sustained activation of peroxisome proliferator-activated receptor alpha (PPAR alpha) in ob/ob mouse liver increases fatty acid oxidation (FAO), which contributes to attenuation of obesity but enhances liver cancer risk. To further evaluate the role of PPAR alpha-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPAR alpha-deficient ob/ob (PPAR alpha(Delta)ob/ob) mice. These mice become strikingly more obese compared to ob/ob littermates, with increased white and brown adipose tissue content and severe hepatic steatosis. Hepatic steatosis becomes more severe in fasted PPAR alpha(Delta)ob/ob mice as they fail to up-regulate FAO systems. PPAR alpha(Delta)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPAR alpha agonist Wy-14,643. Although PPAR alpha(Delta)ob/ob mice are severely obese, there was no significant increase in liver tumor incidence, even when maintained on a diet containing Wy-14,643. We conclude that sustained PPAR alpha activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPAR alpha in ob/ob mice aggravates obesity and hepatic steatosis. However, it does not lead to liver tumor development because of reduction in FAO and energy burning.