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

Lookup NU author(s): Dr Gillian Patman, Professor Loranne Agius, Douglas Hui, Dr Despoina Televantou, Professor Helen ReevesORCiD


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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.

Publication metadata

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

Year: 2013

Volume: 58

Issue: 5

Pages: 1000-1006

Print publication date: 23/01/2013

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier


DOI: 10.1016/j.jhep.2013.01.020


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Funder referenceFunder name
Einstein Diabetes Research and Training Center
European Association for the Study of the Liver (EASL) Sheila Sherlock Short-Term Fellowship
Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) of the Japan Society for the Promotion of Science (JSPS)
Swiss National Fund
Takeda Science Foundation
Deutsche Forschungsgemeinschaft, DFG
IFORES program of the University of Essen
AA017067National Institutes of Health (NIH)
DK37340National Institutes of Health (NIH)
DK56621National Institutes of Health (NIH)
Health-F2-2009-241762European Union