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

Lars P. Bechmann, Diana Vetter, Junichi Ishida, Rebekka A. Hannivoort, Ursula E. Lang, Peri Kocabayoglu, M. Isabel Fiel, Ursula Muñoz, Gillian L. Patman, Fengxia Ge, Shoshana Yakar, Xiaosong Li, Loranne Agius, Young Min Lee, Weijia Zhang, Kei Yiu Hui, Despina Televantou, Gary J. Schwartz, Derek Leroith, Paul D. Berk & 4 others Ryozo Nagai, Toru Suzuki, Helen L. Reeves, Scott L. Friedman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1000-1006
Number of pages7
JournalJournal of Hepatology
Volume58
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

PPAR alpha
Peroxisome Proliferator-Activated Receptors
Transcriptional Activation
Liver
High Fat Diet
Glucose
Hepatocytes
MicroRNAs
Messenger RNA
Insulin
Lipids
Fatty Liver
Glucose Tolerance Test
Lipid Metabolism
Adipocytes
Genes
Insulin Resistance
Adipose Tissue
Cultured Cells
Homeostasis

Keywords

  • CD36
  • KLF6
  • miRNA-10b
  • NAFLD
  • PEPCK
  • PPARα
  • TRB3

ASJC Scopus subject areas

  • Hepatology

Cite this

Bechmann, L. P., Vetter, D., Ishida, J., Hannivoort, R. A., Lang, U. E., Kocabayoglu, P., ... Friedman, S. L. (2013). Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. Journal of Hepatology, 58(5), 1000-1006. https://doi.org/10.1016/j.jhep.2013.01.020

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. / Bechmann, Lars P.; Vetter, Diana; Ishida, Junichi; Hannivoort, Rebekka A.; Lang, Ursula E.; Kocabayoglu, Peri; Fiel, M. Isabel; Muñoz, 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.

In: Journal of Hepatology, Vol. 58, No. 5, 05.2013, p. 1000-1006.

Research output: Contribution to journalArticle

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 2013, 'Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis', Journal of Hepatology, vol. 58, no. 5, pp. 1000-1006. https://doi.org/10.1016/j.jhep.2013.01.020
Bechmann LP, Vetter D, Ishida J, Hannivoort RA, Lang UE, Kocabayoglu P et al. Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. Journal of Hepatology. 2013 May;58(5):1000-1006. https://doi.org/10.1016/j.jhep.2013.01.020
Bechmann, Lars P. ; Vetter, Diana ; Ishida, Junichi ; Hannivoort, Rebekka A. ; Lang, Ursula E. ; Kocabayoglu, Peri ; Fiel, M. Isabel ; Muñoz, 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. / Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. In: Journal of Hepatology. 2013 ; Vol. 58, No. 5. pp. 1000-1006.
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T1 - Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis

AU - Bechmann, Lars P.

AU - Vetter, Diana

AU - Ishida, Junichi

AU - Hannivoort, Rebekka A.

AU - Lang, Ursula E.

AU - Kocabayoglu, Peri

AU - Fiel, M. Isabel

AU - Muñoz, Ursula

AU - Patman, Gillian L.

AU - Ge, Fengxia

AU - Yakar, Shoshana

AU - Li, Xiaosong

AU - Agius, Loranne

AU - Lee, Young Min

AU - Zhang, Weijia

AU - Hui, Kei Yiu

AU - Televantou, Despina

AU - Schwartz, Gary J.

AU - Leroith, Derek

AU - Berk, Paul D.

AU - Nagai, Ryozo

AU - Suzuki, Toru

AU - Reeves, Helen L.

AU - Friedman, Scott L.

PY - 2013/5

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N2 - 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.

AB - 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.

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KW - TRB3

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