Abstract
Cyclic AMP-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor expressed in the liver and small intestine. The activity of CREBH is regulated not only at the transcriptional level but also at the posttranslational level. CREBH governs triglyceride metabolism in the liver by controlling gene expression, with effects including the oxidation of fatty acids, lipophagy, and the expression of apolipoproteins related to the lipoprotein lipase activation and suppression of lipogenesis. The activation and functions of CREBH are controlled in response to the circadian rhythm. On the other hand, intestinal CREBH downregulates the absorption of lipids from the diet. CREBH deficiency in mice leads to severe hypertriglyceridemia and fatty liver in the fasted state and while feeding a high-fat diet. Therefore, when crossing CREBH knockout (KO) mice with an atherosclerosis model, low-density lipoprotein receptor KO mice, these mice exhibit severe atherosclerosis. This phenotype is seen in both liver- and small intestine-specific CREBH KO mice, suggesting that CREBH controls lipid homeostasis in an enterohepatic interaction. This review highlights that CREBH has a crucial role in systemic lipid homeostasis to integrate cellular functions related to lipid metabolism.
Highlights
Cyclic AMP-responsive element-binding protein 3-like 3 (CREB3L3, encoding the CREBH protein) is expressed in only the liver and small intestine
Hepatic CREBH directly and indirectly controls gene expression related to lipid metabolism, resulting in the maintenance of hepatic lipid metabolism
CREBH participates in enterohepatic interactions to maintain systemic lipid metabolism
Summary
Cyclic AMP-responsive element-binding protein 3-like 3 (CREB3L3, encoding the CREBH protein) is expressed in only the liver and small intestine. The transmembrane domain of the CREBH protein is cleaved by the site-1 and site-2 proteases in the Golgi apparatus, producing the active form of the CREBH protein and subsequently transporting it to the nucleus [1]. CREBH has a high homology with the cAMP response element-binding protein (CREB)/Activating transcription factor (ATF) family of molecules via its b-Zip domain. CR binds to both the CRE and box-B sequences in the promoter region to activate gen pression to the cAMP response element (CRE) sequence. CREBH binds to both the CRE and mRNA isregion apparently increased by peroxisome proliferator-activ box-BHepatic sequencesCrebH in the promoter to activate gene expression. CREBH controls fasting-induced gene expression in the liver and maintains nutrient condition to adapt to fasting.
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