Park Jung Eun, Lee Mikang, Mifflin Ryan, Lee Yoon Kwang
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
Am J Physiol Gastrointest Liver Physiol. 2016 May 15;310(10):G799-807. doi: 10.1152/ajpgi.00343.2015. Epub 2016 Mar 11.
Deficiency of the orphan nuclear hormone receptor small heterodimer partner (SHP, NR0B2) protects mice from diet-induced hepatic steatosis, in part, via repression of peroxisome proliferator-activated receptor (PPAR)-γ2 (Pparg2) gene expression. Alcoholic fatty liver diseases (AFLD) share many common pathophysiological features with non-AFLD. To study the role of SHP and PPARγ2 in AFLD, we used a strategy of chronic ethanol feeding plus a single binge ethanol feeding to challenge wild-type (WT) and SHP-null (SHP(-/-)) mice with ethanol. The ethanol feeding induced liver fat accumulation and mRNA expression of hepatic Pparg2 in WT mice, which suggests that a high level of PPARγ2 is a common driving force for fat accumulation induced by ethanol or a high-fat diet. Interestingly, ethanol-fed SHP(-/-) mice displayed hepatic fat accumulation similar to that of ethanol-fed WT mice, even though their Pparg2 expression level remained lower. Mortality of SHP(-/-) mice after ethanol binge feeding was significantly reduced and their acetaldehyde dehydrogenase (Aldh2) mRNA level was higher than that of their WT counterparts. After an intoxicating dose of ethanol, SHP(-/-) mice exhibited faster blood ethanol clearance and earlier wake-up time than WT mice. Higher blood acetate, the end product of ethanol metabolism, and lower acetaldehyde levels were evident in the ethanol-challenged SHP(-/-) than WT mice. Ethanol-induced inflammatory responses and lipid peroxidation were also lower in SHP(-/-) mice. The current data show faster ethanol catabolism and extra fat storage through conversion of acetate to acetyl-CoA before its release into the circulation in this ethanol-feeding model in SHP(-/-) mice.
孤儿核激素受体小异源二聚体伴侣（SHP，NR0B2）的缺乏可部分通过抑制过氧化物酶体增殖物激活受体（PPAR）-γ2（Pparg2）基因表达来保护小鼠免受饮食诱导的肝脂肪变性。酒精性脂肪肝病（AFLD）与非酒精性脂肪肝病有许多共同的病理生理特征。为了研究SHP和PPARγ2在AFLD中的作用，我们采用了慢性乙醇喂养加单次暴饮乙醇喂养的策略，用乙醇对野生型（WT）和SHP基因敲除（SHP(-/-)）小鼠进行挑战。乙醇喂养诱导了WT小鼠肝脏脂肪堆积和肝脏Pparg2的mRNA表达，这表明高水平的PPARγ2是乙醇或高脂饮食诱导脂肪堆积的共同驱动力。有趣的是，乙醇喂养的SHP(-/-)小鼠表现出与乙醇喂养的WT小鼠相似的肝脏脂肪堆积，尽管它们的Pparg2表达水平仍然较低。乙醇暴饮喂养后SHP(-/-)小鼠的死亡率显著降低，其乙醛脱氢酶（Aldh2）mRNA水平高于WT小鼠。给予中毒剂量的乙醇后，SHP(-/-)小鼠比WT小鼠表现出更快的血液乙醇清除率和更早的苏醒时间。在乙醇挑战的SHP(-/-)小鼠中，乙醇代谢终产物血液乙酸水平较高，乙醛水平较低，这一点比WT小鼠明显。乙醇诱导的炎症反应和脂质过氧化在SHP(-/-)小鼠中也较低。目前的数据表明，在这个乙醇喂养模型中，SHP(-/-)小鼠通过将乙酸转化为乙酰辅酶A在其释放到循环之前进行更快的乙醇分解代谢和额外的脂肪储存。
