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

Abstract

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...

Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr −/− Mice

“…We have previously shown that CREBH knockout mice exhibit hypertriglyceridemia in association with decreased production of apoA-IV, apoA-V, and apoC-II apolipoproteins 23 . In addition, hepatic CREBH was activated in mice fed with atherogenic Paigen diet or a high-fat and high-cholesterol western diet 26, 27 . We also showed that hepatic apoA-I mRNA level was reduced in CREBH knockout mice, and increased by CREBH overexpression in primary mouse hepatocytes, suggesting the possibility that CREBH might play a role in HDL metabolism 26 .…”

Apolipoprotein A-IV: a protein intimately involved in metabolism

“…Bile diversion abolishes the circadian rhythm of lymphatic apoA-IV output, thus suggesting that bile is a major determinant of the circadian rhythm of lymph apoA-IV, probably due to its necessity for luminal lipid digestion and thus absorption and chylomicron secretion. It should also be noted that lymph apoA-IV output in the fasting state is maintained by bile fl ow, possibly as a supply of phospholipids as well (CREB) family of transcription factors have been shown to increase APOA4 expression ( 36,48 ) and specifi c binding sites for CREBH were identifi ed proximal to both human and mouse APOA4 genes ( 48 ). Interestingly, one of the CREB members, LUMAN (CREB3), increased APOA4 expression ‫ف‬ 5-fold in dendritic cells without affecting other members of the gene cluster ( 36 ), but the physiological importance of apoA-IV protein in these cells remains to be investigated.…”

Circadian regulators of intestinal lipid absorption

“…apoAIV expression is increased after the overexpression of CREBH in the liver and in cultured cells. High-fat diet induces steatosis in the liver leading to increased expression of CREBH and apoAIV ( 72,73 ). Fasting is known to induce CREBH and apoAIV expression in the liver.…”

“…Recently it has been shown that cAMP responsive elementbinding protein, hepatocyte specifi c (CREBH) regulates apoAIV expression by binding to two CREBH elements present in the apoAIV promoter ( 72 ). CREBH is an ER membrane anchored bZIP transcription factor that is mainly expressed in the liver and intestine ( 72,73 ).…”

“…CREBH is an ER membrane anchored bZIP transcription factor that is mainly expressed in the liver and intestine ( 72,73 ). CREBH deficiency reduces apoAIV expression in the liver and intestine.…”