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. 2018 May 8;19(5):1396.
doi: 10.3390/ijms19051396.

CREBH Regulates Systemic Glucose and Lipid Metabolism

Free PMC article

CREBH Regulates Systemic Glucose and Lipid Metabolism

Yoshimi Nakagawa et al. Int J Mol Sci. .
Free PMC article


The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL) activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα), has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα) in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine.

Keywords: CREBH; FGF21; LXRα; PPARα; SREBP; lipid metabolism; transcription.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Scheme of Fgf21 transcriptional regulation by the interaction between CREBH and PPARα. Fgf21 promoter has a PPARα-binding site (PPRE) and a CREBH-binding site (CHRE), which are partially overlapped. (A) CREBH and PPARα directly bind to their own binding sites on the Fgf21 promoter. (B) CREBH regulates PPARα transcriptional activity as a co-activator and by peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) recruiting. (C) CREBH and PPARα form a complex on the Fgf21 promoter and synergistically activate Fgf21 expression.

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