Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.
OBJECTIVE
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.
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, United States.
Lars P
LP
Bechmann
Diana
D
Vetter
Junichi
J
Ishida
Rebekka A
RA
Hannivoort
Ursula E
UE
Lang
Peri
P
Kocabayoglu
M Isabel
MI
Fiel
Ursula
U
Muñoz
Gillian L
GL
Patman
Fengxia
F
Ge
Shoshana
S
Yakar
Xiaosong
X
Li
Loranne
L
Agius
Young-Min
YM
Lee
Weijia
W
Zhang
Kei Yiu
KY
Hui
Despina
D
Televantou
Gary J
GJ
Schwartz
Derek
D
LeRoith
Paul D
PD
Berk
Ryozo
R
Nagai
Toru
T
Suzuki
Helen L
HL
Reeves
Scott L
SL
Friedman
D000818:Animals; D002478:Cells, Cultured; D015331:Cohort Studies; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000502:physiology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
D007328:Insulin; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D047493:PPAR alpha; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose