The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

Lee, Jung Hoon; Giannikopoulos, Petros; Duncan, Stephen A.; Wang, Jian; Johansen, Christopher T.; Brown, J.; Plutzky, Jorge; Hegele, Robert A.; Glimcher, Laurie H.; Lee, Ann–Hwee

doi:10.1038/nm.2347

Cited by 178 publications

(282 citation statements)

References 20 publications

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“…Consistently, forced expression of CREBH in the liver causes hepatic lipid accumulation, although TG levels in the blood decrease Xu et al 2015). In addition, CREBH promotes expression of lipoprotein lipase (Lpl) coactivators apolipoprotein C2 (Apoc2), Apoa4, and Apoa5 and concurrently down-regulates Lpl inhibitor Apoc3 (Lee et al 2011b). As a result, Crebl3 −/− mice display hypertriglyceridemia due to inefficient TG clearance.…”

Section: Additional Tfsmentioning

confidence: 97%

“…As a result, Crebl3 −/− mice display hypertriglyceridemia due to inefficient TG clearance. Furthermore, multiple nonsynonymous mutations in CREB3L3 are associated with extreme hypertriglyceridemia, suggesting a pivotal role of CREBH in human TG metabolism (Lee et al 2011b). In addition to lipid metabolism, CREBH promotes hepatic gluconeogenesis by inducing expression of gluconeogenic enzyme in a CRTC2-dependent manner ).…”

Section: Additional Tfsmentioning

confidence: 99%

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Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Section: Additional Tfsmentioning

confidence: 97%

Section: Additional Tfsmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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“…Studies in cell culture and animal models have identified several transcription factors including PPAR-α, liver X receptor-α (LXR-α), hepatocyte nuclear factor 4-α (HNF4-α) and upstream stimulatory factor (USF1) that contribute to the regulation of APOA5 expression [65,66]. In a recent study, Lee et al [67] identified cyclic AMP responsive element binding protein H (CREB-H) as a regulator of several proteins affecting lipolysis, including apoAV, apoCII and apoCIII. Three isoforms of PPARs (α, β, γ) have been described.…”

Section: Apolipoproteins and Chylomicron Synthesismentioning

confidence: 99%

Recent advances in physiological lipoprotein metabolism

Ramasamy

2014

Clinical Chemistry and Laboratory Medicine (CCLM)

178

154

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Abstract:Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and posttranscriptional level. Proprotein convertase subtilisin/ kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDLcholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several transcription factors, including the liver X receptor and sterol regulatory element binding protein. This review summarizes recent advances in knowledge of the molecular mechanisms regulating lipoprotein metabolism.Keywords: ABCA1; angiopoietin-like proteins; apoC; apoAI; apolipoprotein E (apoE); cholesterol ester transfer protein; chylomicron; LDL receptor; lecithin cholesterol acyl transferase; lipoprotein(a); lipoprotein lipase; microsomal transfer protein; propertin convertase subtilisin/ kexin type 9; SR-BI; phospholipid transfer protein; very low density lipoproteins (VLDL). Abstract 1695

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“…Recently, a role for CREBH in triacylglycerol metabolism has been suggested. Genetically CREBH-deficient mice showed higher plasma triacylglycerol concentrations than wild-type mice, and this was due to inefficient triacylglycerol clearance catalysed by lipoprotein lipase [25]. More recently, Zhang et al showed that disruption of CREBH activity leads to massive accumulation of hepatic lipid metabolites and significant increases in plasma triacylglycerol levels in animals fed with an atherogenic high-fat diet (HFD) [26].…”

Section: Introductionmentioning

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 transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

Cited by 178 publications

References 20 publications

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Recent advances in physiological lipoprotein metabolism

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

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