Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis.
Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis.
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DOI：
10.1002/hep.26946
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Kowdley KV
中科院分区：
文献类型：
--
作者：
Handa P;Maliken BD;Nelson JE;Morgan-Stevenson V;Messner DJ;Dhillon BK;Klintworth HM;Beauchamp M;Yeh MM;Elfers CT;Roth CL;Kowdley KV
肥胖和脂联素缺乏与非酒精性脂肪性肝病（NAFLD）的发生有关。本研究的目的是在肥胖糖尿病小鼠模型中确定体重增加、脂联素信号传导和非酒精性脂肪性肝炎（NASH）发展之间的关系。给予瘦素受体缺陷（Leprdb/db）和C57 BL/6小鼠高不饱和脂肪（HF）（61%）饮食或正常食物5或10周。使用脂肪变性、炎症和气球样变评分评价肝组织学。分析血清、脂肪组织和肝脏的代谢参数、信使RNA（mRNA）和蛋白质水平的变化。Leprdb/db HF小鼠在每个时间点发展为显著的肥胖、肝脂肪变性，并且超过50%进展为NASH。血清脂联素水平与体重呈强负相关（r =-0.82; P < 0.0001），脂联素水平是NASH的独立预测因子（13.6 μg/mL; P < 0.05;受试者工作曲线下面积（AUROC）= 0.84）。NASH小鼠的白色脂肪组织的特征在于与氧化应激相关的基因表达增加、巨噬细胞浸润、脂联素减少和脂质代谢受损。HF lepr db/db NASH小鼠表现出肝脏脂联素信号传导减少，表现为脂联素受体-2水平降低、腺苷一磷酸活化蛋白激酶（AMPK）失活以及参与线粒体生物合成和β-氧化的基因（Cox 4、Nrf 1、Pgc 1 α、Pgc 1 β和Tfam）表达降低。与此相反，重组脂联素管理上调AML-12肝细胞线粒体基因的表达，有或没有脂质负荷。喂食高不饱和脂肪饮食的Leprdb/db小鼠通过脂联素耗竭发生体重增加和NASH，这与脂肪组织炎症和肝线粒体功能障碍相关。我们认为，这种NASH小鼠模型可能为人类NASH的发展机制提供新的见解。
Obesity and adiponectin depletion have been associated with the occurrence of nonalcoholic fatty liver disease (NAFLD). The goal of this study was to identify the relationship between weight gain, adiponectin signaling, and development of nonalcoholic steatohepatitis (NASH) in an obese, diabetic mouse model. Leptin-receptor deficient (Leprdb/db) and C57BL/6 mice were administered a diet high in unsaturated fat (HF) (61%) or normal chow for 5 or 10 weeks. Liver histology was evaluated using steatosis, inflammation, and ballooning scores. Serum, adipose tissue, and liver were analyzed for changes in metabolic parameters, messenger RNA (mRNA), and protein levels. Leprdb/db HF mice developed marked obesity, hepatic steatosis, and more than 50% progressed to NASH at each timepoint. Serum adiponectin level demonstrated a strong inverse relationship with body mass (r = −0.82; P < 0.0001) and adiponectin level was an independent predictor of NASH (13.6 μg/mL; P < 0.05; area under the receiver operating curve (AUROC) = 0.84). White adipose tissue of NASH mice was characterized by increased expression of genes linked to oxidative stress, macrophage infiltration, reduced adiponectin, and impaired lipid metabolism. HF lepr db/db NASH mice exhibited diminished hepatic adiponectin signaling evidenced by reduced levels of adiponectin receptor-2, inactivation of adenosine monophosphate activated protein kinase (AMPK), and decreased expression of genes involved in mitochondrial biogenesis and β-oxidation (Cox4, Nrf1, Pgc1α, Pgc1β and Tfam). In contrast, recombinant adiponectin administration up-regulated the expression of mitochondrial genes in AML-12 hepatocytes, with or without lipid-loading. Leprdb/db mice fed a diet high in unsaturated fat develop weight gain and NASH through adiponectin depletion, which is associated with adipose tissue inflammation and hepatic mitochondrial dysfunction. We propose that this murine model of NASH may provide novel insights into the mechanism for development of human NASH.
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DOI：
10.1111/j.1440-1746.2009.05996.x
发表时间：
2009-10-01
影响因子：
4.1
作者：
Larter, Claire Z.;Yeh, Matthew M.;Farrell, Geoffrey C.
通讯作者：
Farrell, Geoffrey C.
影响因子：
4.8
作者：
Mandal, Palash;Pratt, Brian T.;Nagy, Laura E.
通讯作者：
Nagy, Laura E.
影响因子：
64.8
作者：
Kahn, Steven E.;Hull, Rebecca L.;Utzschneider, Kristina M.
通讯作者：
Utzschneider, Kristina M.
DOI：
10.1111/j.1440-1746.2009.05870.x
发表时间：
2009-08-01
影响因子：
4.1
作者：
Ahmed, Umbreen;Redgrave, Trevor G.;Oates, Phillip S.
通讯作者：
Oates, Phillip S.
影响因子：
4.4
作者：
Aguilera, CM;Ramirez-Tortosa, CL;Ramirez-Tortosa, MC
通讯作者：
Ramirez-Tortosa, MC