The sterol regulatory element binding proteins (SREBPs) have been studied as key modulators of lipid metabolism but emerging data indicate they are involved in additional cellular pathways and processes. In mammals, there are three major SREBP isoforms encoded by two unlinked genes. The SREBP-1 gene has two isomers that only differ at their amino-terminal regions. The SREBP-1a amino terminal domain is longer, functions as a strong activation domain and interacts well with non-DNA binding transcriptional co-activators. In contrast, the shorter SREBP-1c amino-terminus is a relatively poor activation domain that interacts weakly with the same co-activators as SREBP-1a. The relative ratios and absolute levels of the mRNAs for the different SREBP-1's vary considerably across different tissues and they have been most studied in the liver where SREBP-1c is regulated by insulin and LXR and is expressed at 10 fold higher levels than SREBP-1a. Little is known about the role of SREBPs outside of the liver and this proposal is focused on the function of SREBP-1 in macrophages where our preliminary studies show SREBP-1a is expressed at 10 fold higher levels than SREBP-1c levels and its expression is regulated by bacterial lipopolysaccharide (LPS). We have generated a new mouse model that has a targeted deficiency of SREBP-1a and our preliminary data indicates that this isoform plays a key role in macrophage function. The focus of this renewal application is to use this new model along with state-of-the art molecular approaches and novel technology to investigate the roles of SREBP-1 in nutrition and metabolism in the macrophage.

Public Health Relevance

The overall goal of this proposal is to investigate the basic mechanism of macrophage lipid metabolism and to decipher the communication between different signaling pathways that must work together to keep cellular metabolism in balance. These studies use a new animal model of disease and state of the art methods and techniques that will uncover previously unappreciated ways that connect nutritional regulation of lipid metabolism to the Immune system with significant relevance to the development and progression of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048044-21
Application #
8516555
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Liu, Lijuan
Project Start
1994-01-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
21
Fiscal Year
2013
Total Cost
$459,459
Indirect Cost
$223,839
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jeon, Tae-Il; Esquejo, Ryan M; Roqueta-Rivera, Manuel et al. (2013) An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. Cell Metab 18:51-61
Im, Seung-Soon; Osborne, Timothy F (2012) Protection from bacterial-toxin-induced apoptosis in macrophages requires the lipogenic transcription factor sterol regulatory element binding protein 1a. Mol Cell Biol 32:2196-202
Chong, Hansook Kim; Biesinger, Jacob; Seo, Young-Kyo et al. (2012) Genome-wide analysis of hepatic LRH-1 reveals a promoter binding preference and suggests a role in regulating genes of lipid metabolism in concert with FXR. BMC Genomics 13:51
Jeon, Tae-Il; Osborne, Timothy F (2012) SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 23:65-72
Blanc, Mathieu; Hsieh, Wei Yuan; Robertson, Kevin A et al. (2011) Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol 9:e1000598
Seo, Young-Kyo; Jeon, Tae-Il; Chong, Hansook Kim et al. (2011) Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy. Cell Metab 13:367-75
Jeon, Tae-Il; Seo, Young-Kyo; Osborne, Timothy F (2011) Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. Biochem J 438:33-7
Im, Seung-Soon; Yousef, Leyla; Blaschitz, Christoph et al. (2011) Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 13:540-9
Im, Seung-Soon; Osborne, Timothy F (2011) Liver x receptors in atherosclerosis and inflammation. Circ Res 108:996-1001
Huang, Yongcheng; He, Shaoqing; Li, John Zhong et al. (2010) A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 107:7892-7

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