The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARα

Danno, Hirosuke; Ishii, Kiyo‐aki; Nakagawa, Yoshimi; Mikami, Motoki; Yamamoto, Takashi; Yabe, Sachiko; Furusawa, Mika; Kumadaki, Shin; Watanabe, Kazuhisa; Shimizu, Hidehisa; Matsuzaka, Takashi; Kobayashi, Kazuto; Takahashi, Akimitsu; Yatoh, Shigeru; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1016/j.bbrc.2009.12.046

Cited by 66 publications

(80 citation statements)

References 10 publications

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“…Glucocorticoid receptor and PPAR ␣ have been implicated in the transcriptional activation of CREBH in response to fasting ( 7,8 ). In contrast, little is known about the regulation of proteolytic activation of CREBH.…”

Section: Discussionmentioning

confidence: 99%

“…However, subsequent studies by several other groups failed to detect proteolytic activation of CREBH by ER stress inducers in stable cell lines expressing exogenous CREBH ( 10, 11 ). On the other hand, hepatic CREBH mRNA is induced by fasting and suppressed by refeeding, which appears to be mediated by glucocorticoid receptor and PPAR ␣ that bind to peroxisome proliferator responsive element (PPRE) and glucocorticoid transcriptional response element on the CREBH promoter ( 7,8,12 ). …”

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confidence: 99%

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Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

Park

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org transcription factor that could bind to cAMP response element (CRE) and activate the transcription driven by CREcontaining promoters, such as rat phosphoenolpyruvate carboxykinase (PEPCK) promoter ( 1, 2 ).Recent studies employing genetic ablation of CREBH or in vivo delivery of sequence-specifi c shRNA revealed that CREBH is involved in a variety of physiological functions of the liver. It has been shown that CREBH is proteolytically activated by ER stress ( 5 ), induced acute phase response genes ( 5 ), and the iron metabolism regulator, hepcidin ( 6 ). It has also been demonstrated that CREBH is induced in the liver of fasted mice ( 7 ), and promotes the transcription of genes involved in gluconeogenesis ( 8 ) and plasma TG clearance ( 9 ).While CREBH controls the expression of a variety of target genes, the upstream signal that activates CREBH and the promoter element mediating the CREBH function remain poorly understood. Despite the postulated roles for CREBH in ER stress-mediated infl ammatory response and hepcidin expression, it remains controversial whether CREBH is indeed activated by ER stress. Zhang et al. ( 5 ) fi rst reported that CREBH was activated by ER stress, in a manner similar to ATF6 ␣ . However, subsequent studies by several other groups failed to detect proteolytic activation of CREBH by ER stress inducers in stable cell lines expressing exogenous CREBH ( 10, 11 ). On the other hand, hepatic CREBH mRNA is induced by fasting and suppressed by refeeding, which appears to be mediated by glucocorticoid receptor and PPAR ␣ that bind to peroxisome proliferator responsive element (PPRE) and glucocorticoid transcriptional response element on the CREBH promoter ( 7,8,12 ). Abstract cAMP responsive element-binding protein H (CREBH) is an endoplasmic reticulum (ER) anchored tran-scription factor that is highly expressed in the liver and small intestine and implicated in nutrient metabolism and proinfl ammatory response. ApoA-IV is a glycoprotein secreted primarily by the intestine and to a lesser degree by the liver. ApoA-IV expression is suppressed in CREBHdefi cient mice and strongly induced by enforced expression of the constitutively active form of CREBH, indicating that CREBH is the major transcription factor regulating Apoa4 gene expression. Here, we show that CREBH directly controls Apoa4 expression through two tandem CREBH binding sites (5 ′ -CCACGTTG-3 ′ ) located on the promoter, which are conserved between human and mouse. Chromatin immunoprecipitation and electrophoretic mobility-shift assays demonstrated specific association of CREBH with the CREBH binding sites. We also demonstrated that a substantial amount of CREBH protein was basally processed to the active nuclear form in normal mouse liver, which was further increased in steatosis induced by high-fat diet or fasting, increasing apoA-IV expression. However, we failed to fi nd signifi cant activation of CREBH in response to ER stress, arguing against the critical role of CREBH in...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

Park

et al. 2014

Journal of Lipid Research

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“…Although the exact metabolic cues that mediate this activation sequence are unknown, 41 cAMP response element-binding protein H expression is enhanced by a number of metabolic conditions, including fasting, insulin resistance, 42 and ER stress, 43 all of which also promote VLDL secretion. 44,45 Thus, it is intriguing to consider that the MTPmediated movement of lipid across the ER membrane [46][47][48] or incorporation into nascent primordial particles in the ER 49 integrates apoA-IV gene expression with VLDL assembly, perhaps via cAMP response element-binding protein H production and/or processing, which then, in turn, serves as the specific signal that regulates apoA-IV transcription.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-IV Expression in Mouse Liver Enhances Triglyceride Secretion and Reduces Hepatic Lipid Content by Promoting Very Low Density Lipoprotein Particle Expansion

VerHague

Cheng

Weinberg

et al. 2013

ATVB

103

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Objective-Previous studies demonstrated that apolipoprotein A-IV (apoA-IV) promotes apoB lipoprotein-mediated triglyceride (TG) secretion in transfected enterocytes and hepatoma cells; however, evidence for a role in lipid transport in vivo is lacking. Using mouse models, we explored the role of apoA-IV in hepatic very low density lipoprotein-mediated lipid efflux under conditions that promote hepatic steatosis. Approach and Results-Hepatic steatosis, induced by either high-fat diet or enhanced de novo lipogenesis caused by transgenic overexpression of SREBP-1a (SREBP-1a Tg ), was associated with up to a 43-fold induction of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r 2 =0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1aTg mice were crossed with Apoa4 knockout mice. With Triton blockade of peripheral lipolysis, SREBP-1aTg /Apoa4 knockout mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1aTg controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted very low density lipoprotein particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 52% increase in the hepatic TG secretion rate, relative to controls, a 38% reduction in liver TG content, and a 43% increase in large diameter (≥120 nm) very low density lipoprotein particles, with no change in apoB secretion. Conclusions-Hepatic

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“…Fenofibrate has beneficial effects on metabolic syndrome by downregulating multiple target genes involved in the pathogenesis of hepatic steatosis [41][42][43]. Recent studies show that fenofibrate induces CREBH production to a level comparable with that observed under fasting conditions [44]. However, the exact molecular mechanism underlying the anti-hepatic steatosis effect of fenofibrate remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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

Min

Jeong

et al. 2012

Diabetologia

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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, AdCrebh 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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The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARα

Cited by 66 publications

References 10 publications

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

Apolipoprotein A-IV Expression in Mouse Liver Enhances Triglyceride Secretion and Reduces Hepatic Lipid Content by Promoting Very Low Density Lipoprotein Particle Expansion

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

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