Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.
Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.
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DOI：
10.1016/j.jhep.2013.01.020
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发表时间：
2013-05
影响因子：
25.7
通讯作者：
Friedman, Scott L.
中科院分区：
文献类型：
--
作者：
Bechmann, Lars P.;Vetter, Diana;Ishida, Junichi;Hannivoort, Rebekka A.;Lang, Ursula E.;Kocabayoglu, Peri;Fiel, M. Isabel;Munoz, Ursula;Patman, Gillian L.;Ge, Fengxia;Yakar, Shoshana;Li, Xiaosong;Agius, Loranne;Lee, Young-Min;Zhang, Weijia;Hui, Kei Yiu;Televantou, Despina;Schwartz, Gary J.;LeRoith, Derek;Berk, Paul D.;Nagai, Ryozo;Suzuki, Toru;Reeves, Helen L.;Friedman, Scott L.
葡萄糖稳态失调和脂质蓄积是非酒精性脂肪性肝病（NAFLD）的特征，但其潜在机制尚不清楚。我们在这里报告，Krüppel样因子6（KLF 6），一种普遍存在的促进脂肪细胞分化的转录因子，也通过转录后激活PPARα信号转导引起NAFLD的代谢异常。对肝细胞特异性KLF 6耗竭（“DeltaHepKlf 6”）或KLF 6杂合性（Klf 6 +/−）小鼠喂食高脂饮食（HFD）或普通饲料8周或16周。进行葡萄糖和胰岛素耐量试验以评估胰岛素敏感性。在培养的细胞中KLF 6的过表达和敲低使得能够阐明潜在的机制。在来自28名NAFLD患者的队列的肝脏样本中，定量KLF 6相关靶基因的表达。KLF 6整体或肝细胞耗竭的小鼠具有降低的体脂含量和改善的葡萄糖和胰岛素耐受性，并且保护免于HFD诱导的脂肪变性。在肝细胞中，KLF 6缺陷减少了PPARα调节基因（Trb 3，Pepck），同时减少了PPARα蛋白，但Pparα-mRNA无变化，这可以通过发现KLF 6抑制miRNA 10 b（导致诱导PPARα）来解释。在伴有晚期疾病和炎症的NAFLD患者中，miRNA 10 b的表达显著下调，而PEPCK mRNA表达上调; KLF 6 mRNA表达也与TRB 3以及PEPCK基因表达相关。KLF 6增加了PPAR α的活性，而KLF 6的缺失导致了PPARα的抑制和与高脂饮食相关的脂质和葡萄糖异常的减弱。这些发现确立了KLF 6作为脂肪肝中肝脏葡萄糖和脂质代谢的新调节剂。
Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. Mice with either hepatocyte-specific depletion of KLF6 (‘DeltaHepKlf6’) or global KLF6 heterozygosity (Klf6 +/−) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα-protein but no change in Pparα-mRNA which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD-patients with advanced disease and inflammation, the expression of miRNA 10b is significantly down-regulated, while PEPCK mRNA is up-regulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. KLF6 increases PPAR -activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.
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影响因子：
25.7
作者：
Ibrahim SH;Akazawa Y;Cazanave SC;Bronk SF;Elmi NA;Werneburg NW;Billadeau DD;Gores GJ
通讯作者：
Gores GJ
影响因子：
4.8
作者：
Leow, Ching Ching;Wang, Bu-er;Gao, Wei-Qiang
通讯作者：
Gao, Wei-Qiang
影响因子：
5.3
作者：
She, P;Shiota, H;Magnuson, MA
通讯作者：
Magnuson, MA
影响因子：
4.8
作者：
Li, D;Yea, S;Walsh, MJ
通讯作者：
Walsh, MJ
影响因子：
29.4
作者：
Miele, Luca;Beale, Gary;Reeves, Helen L.
通讯作者：
Reeves, Helen L.