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Diabetologia
Published in: Diabetologia 2/2013

01-02-2013 | Article

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Authors: A.-K. Min, J. Y. Jeong, Y. Go, Y.-K. Choi, Y.-D. Kim, I.-K. Lee, K.-G. Park

Published in: Diabetologia | Issue 2/2013

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Abstract

Aims/hypothesis

Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis.

Methods

The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production.

Results

Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, Ad-Crebh inhibited insulin- and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo.

Conclusions/interpretation

These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.
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Metadata
Title
cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis
Authors
A.-K. Min
J. Y. Jeong
Y. Go
Y.-K. Choi
Y.-D. Kim
I.-K. Lee
K.-G. Park
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 2/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2771-2

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