High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.
High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.
复制标题
DOI：
10.1111/j.1582-4934.2010.01128.x
复制
发表时间：
2011-06
影响因子：
5.3
通讯作者：
Sookoian S
中科院分区：
文献类型：
--
作者：
Carabelli J;Burgueño AL;Rosselli MS;Gianotti TF;Lago NR;Pirola CJ;Sookoian S
线粒体DNA(MtDNA)拷贝数在代谢综合征相关表型的病理生理学中起关键作用，但其在非酒精性脂肪性肝病(NAFLD)中的作用尚不清楚。在高脂诱导的NAFLD大鼠模型中，我们评估了可能参与调节肝脏线粒体DNA含量的分子机制。特别是，我们验证了肝脏线粒体DNA拷贝数与肝脏HIF-1α表达相关的假设。分别给予标准饲料(SCD，n=10)和高脂饲料(HFD，n=15)喂养20周。随后，以核DNA(NDNA)为参照物，采用实时荧光定量聚合酶链式反应进行mtDNA定量。HFD可引起大鼠肝脏mtDNA/nDNA比值显著升高，且与肝脏甘油三酯含量呈显著正相关(R：0.29，P<；0.05)。肝线粒体DNA/核DNA比值与肝组织HIF-1α基因表达显著相关(R=0.37P&0.001)，肝组织HIF-1α基因表达明显高于对照组。此外，肝细胞色素C氧化酶亚基IV亚型1(COX4I1)的mRNA表达也与肝线粒体DNA含量呈正相关。参与线粒体生物发生调控的转录因子PGC-1α(α)和PGC-1β、核呼吸因子-1(NRF-1)、过氧化物酶体增殖物激活受体δ和TFAM的表达与肝脏线粒体DNA含量无关。HIF-1α介导的线粒体DNA拷贝数增加与肝细胞凋亡和氧化应激无关。综上所述，我们发现高脂饲料通过低氧诱导因子-1α促进低氧条件下肝脏线粒体生物合成的增加，可能是为了增强线粒体的功能以及调节代谢负荷。
Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1α. Rats were given either standard chow diet (SCD, n= 10) or high-fat diet (HFD, n= 15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, P < 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1β, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load.
登录
查看更多内容
细胞角蛋白-18片段水平为非酒精性脂肪性肝炎的无创生物标志物：一项多中心验证研究。
影响因子：
13.5
作者：
Feldstein, Ariel E.;Wieckowska, Anna;Lopez, A. Rocio;Liu, Yao-Chang;Zein, Nizar N.;McCullough, Arthur J.
通讯作者：
McCullough, Arthur J.
影响因子：
6
作者：
Piguet, Anne-Christine;Stroka, Deborah;Dufour, Jean-Francois
通讯作者：
Dufour, Jean-Francois
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
7.4
作者：
Lee, Heung M.;Greeley, George H., Jr.;Englander, Ella W.
通讯作者：
Englander, Ella W.
影响因子：
14.9
作者：
Ruijter JM;Ramakers C;Hoogaars WM;Karlen Y;Bakker O;van den Hoff MJ;Moorman AF
通讯作者：
Moorman AF