CREB-H is an endoplasmic reticulum (ER)-bound transcription factor that is highly and selectively expressed only in the liver and the small intestine. CREB-H activation requires a sequential cleavage of its precursor protein by Golgi proteases that liberate the mature N-terminal portion of the protein, which localizes to the nucleus to act as a transcriptional transactivator. CREB-H is induced by fatty acids, the fatty acid oxidation regulator PPAR1, and fasting in the liver, suggesting that it might participate in nutrient and energy metabolism. We demonstrated that CREB-H is required for the maintenance of normal trigylceride (TG) levels in vivo. CREB-H is induced in the liver by fasting and controls a subset of genes that are critical for TG and lipoprotein metabolism. CREB-H deficient mice displayed severe hypertriglyceridemia secondary to inefficient TG clearance catalyzed by lipoprotein lipase (LPL). Genetic profiling revealed that CREB-H deficiency was associated with decreased expression of the LPL coactivators, Apoc2, Apoa4, and Apoa5 apolipoproteins and concurrent augmentation of the LPL inhibitor, Apoc3. Multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein were identified in patients with extreme hypertriglyceridemia. We establish CREB-H as a novel transcription factor that governs TG metabolism in rodents and humans. The current proposal aims to further investigate the function and mechanism of action of CREB-H in lipid metabolism. We propose to address the following questions:
Aim 1. What is the organ specific function of CREB-H in liver and small intestine, as assessed using conditional CREB-H knock-out mice that selectively lack CREB-H in these organs? Aim 2 and 3. CREB-H and PPAR1 share common target genes that are involved in fatty acid oxidation. What is the functional relationship between CREB-H and PPAR1? Does CREB-H play a role in hepatic steatosis? Given the induction of PCPCK by CREB-H, is CREB-H required for glucose homeostasis? What is the universe of CREB-H targets genes in the liver and intestine? What nutritional and hormonal signals regulate CREB-H, and how CREB-H activation can be achieved at multiple levels, which include transcriptional activation, Golgi translocation, and other post-translational modifications. The mode of CREB-H activation appears be distinct in liver and small intestine, and we will further investigate the precise mechanisms that account for this. Given that CREB-H deficiency resulted in hyperlipidemia, would the augmentation of CREB-H activity be beneficial in the treatment of dyslipidemia? We will address this question by inducible overexpression of constitutively active CREB-H.
Aim 4. Finally, what is the molecular mechanism for hypertriglyceridemia caused by mutations in CREB3L3 in patients? We envision that these studies will uncover novel signaling pathways that may lead to the discovery of potential targets for developing novel therapeutics for dislipidemia.

Public Health Relevance

We have much left to learn about the genes that regulate lipid metabolism and contribute to human dyslipidemias. We have recently demonstrated that CREB-H is a novel key transcription factor controlling triglyceride metabolism both in mouse and human by investigating CREB-H deficient mice and identifying CREB-H (CREB3L3) mutations in patients with hypertriglyceridemia. The current proposal aims to define the precise molecular mechanisms that explain the function of CREB-H in lipid metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089211-02
Application #
8313880
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Pawlyk, Aaron
Project Start
2011-08-06
Project End
2012-08-31
Budget Start
2012-06-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$351,263
Indirect Cost
$133,763
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Cheng, Dongmei; Xu, Xu; Simon, Trang et al. (2016) Very Low Density Lipoprotein Assembly Is Required for cAMP-responsive Element-binding Protein H Processing and Hepatic Apolipoprotein A-IV Expression. J Biol Chem 291:23793-23803
Park, Jong-Gil; Xu, Xu; Cho, Sungyun et al. (2016) CREBH-FGF21 axis improves hepatic steatosis by suppressing adipose tissue lipolysis. Sci Rep 6:27938
Park, Jong-Gil; Xu, Xu; Cho, Sungyun et al. (2016) Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr-/- Mice. Arterioscler Thromb Vasc Biol 36:1772-81
So, Jae-Seon; Cho, Sungyun; Min, Sang-Hyun et al. (2015) IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis. Mol Cell Biol 35:2761-70
Xu, Xu; Park, Jong-Gil; So, Jae-Seon et al. (2015) Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis. Hepatology 61:857-69
Fedeles, Sorin V; So, Jae-Seon; Shrikhande, Amol et al. (2015) Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. J Clin Invest 125:1955-67
Xu, Xu; Park, Jong-Gil; So, Jae-Seon et al. (2014) Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH. J Lipid Res 55:850-9
Xu, Xu; So, Jae-Seon; Park, Jong-Gil et al. (2013) Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin Liver Dis 33:301-11
Cho, Jin A; Lee, Ann-Hwee; Platzer, Barbara et al. (2013) The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13:558-69
Lee, Ann-Hwee (2012) The role of CREB-H transcription factor in triglyceride metabolism. Curr Opin Lipidol 23:141-6

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