Post-transcriptional activation of PPM alpha by KLF6 in hepatic steatosis

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^*

来源：Journal of Hepatology, 2013, 58(5): 1000-1006.

DOI：10.1016/j.jhep.2013.01.020

• KLF6
• PPAR alpha
• TRB3
• PEPCK
• CD36
• miRNA-10b
• NAFLD

Background %26 Aims: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Kruppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPAR alpha-signaling. %26lt;br%26gt;Methods: Mice with either hepatocyte-specific depletion of KLF6 (%26apos;Delta HepKlf6%26apos;) 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. %26lt;br%26gt;Results: 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 PPARa-regulated genes (Trb3, Pepck) with diminished PPARa, protein but no change in Ppara mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARa. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. %26lt;br%26gt;Conclusions: MI6 increases PPAR alpha, activity, whereas KLF6 loss leads to PPARa 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.

• 出版日期2013-5