Lookup NU author(s): Dr Gillian Patman,
Professor Loranne Agius,
Dr Despoina Televantou,
Professor Helen Reeves
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Background & Aims: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. Methods: Mice with either hepatocyte-specific depletion of KLF6 (‘ΔHepKlf6’) 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. 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 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 downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. Conclusions: KLF6 increases PPARα 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.
Author(s): Bechmann LP, Vetter D, Ishida J, Hannivoort RA, Lang UE, Kocabayoglu P, Fiel MI, Muñoz U, Patman GL, Ge F, Yakar S, Li X, Agius L, Lee YM, Zhang W, Hui KY, Televantou D, Schwartz GJ, Leroith D, Berk PD, Nagai R, Suzuki T, Reeves HL, Friedman SL
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Print publication date: 23/01/2013
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
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