Our research program is focused on mechanisms by which nutritional input and metabolic demand regulate genes of lipid metabolism. In mammals there are three SREBPs that are major regulators of genes in lipid metabolism. SREBP-1a and 1c are encoded by overlapping mRNAs from a single gene and SREBP-2 is transcribed from a distinct gene. SREBPs bind DMA as dimers through their bHLHLZ domains and they have the potential to homo and heterodimerize with one another. In this proposal, we evaluate the specific functions of the individual homo and heterodimers in activation of SREBP target genes by combining cell culture and animal models to obtain a multi-level perspective on lipid regulation by these complex transcription factors.
In Aim 1 we engineer transformed cells that simultaneously express only two different SREBP isoforms (each under the control of a separate regulatory inducer) in order to examine the functional roles of the individual SREBP homo and heterodimers in binding to and activation of target genes.
In Aim 2 we move away from artificial manipulation of the individual SREBPs and instead focus on the consequences of dietary fluctuation and pharmacologic challenge to SREBP binding and activation of target genes in a mouse model.
In Aim 3 we combine the strengths of artificial manipulation of SREBPs and animal models to study mice that over-express both 1a and 1c simultaneously. This is of particular interest because it will allow us to test our hypothesis that 1c attenuates 1 a activity (based on cell culture studies) in an animal model. These studies are highly significant for two reasons: 1) understanding the function of the individual SREBPs will predict how physiologic or pharmacologic changes in their expression alter lipid metabolism in animals, 2) The human genome contains only 30,000 individual genes, so gene number is insufficient to account for the incredible complexity of an individual human being. Expression of multiple proteins from overlapping mRNAs (like SREBP-1a and -1c) and differential association of protein monomers into distinct dimers/complexes with unique functional properties (also a property of SREBPs) are two mechanisms that significantly increase genomic coding potential. Thus, the SREBP system provides a well-defined experimental model to evaluate molecular mechanisms that contribute to the expansion of genome complexity from the DNA to protein level. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL048044-16S1
Application #
7681891
Study Section
Special Emphasis Panel (ZRG1-EMNR-D (02))
Program Officer
Liu, Lijuan
Project Start
1994-01-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
16
Fiscal Year
2008
Total Cost
$56,952
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Key, Chia-Chi C; Liu, Mingxia; Kurtz, C Lisa et al. (2017) Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. Cell Rep 19:2116-2129
Wang, Ying; Hu, Haiyan; Li, Xiaoman (2016) MBMC: An Effective Markov Chain Approach for Binning Metagenomic Reads from Environmental Shotgun Sequencing Projects. OMICS 20:470-9
Roqueta-Rivera, Manuel; Esquejo, Ryan M; Phelan, Peter E et al. (2016) SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation. Cell Metab 24:474-484
Jeon, Tae-Il; Osborne, Timothy F (2016) miRNA and cholesterol homeostasis. Biochim Biophys Acta 1861:2041-2046
Ding, Jun; Li, Xiaoman; Hu, Haiyan (2016) TarPmiR: a new approach for microRNA target site prediction. Bioinformatics 32:2768-75
Li, Xin; Zheng, Yiyu; Hu, Haiyan et al. (2016) Integrative analyses shed new light on human ribosomal protein gene regulation. Sci Rep 6:28619
Kim, Kwang-Youn; Jang, Hyun-Jun; Yang, Yong Ryoul et al. (2016) SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy. Sci Rep 6:35732
Zhao, Changyong; Li, Xiaoman; Hu, Haiyan (2016) PETModule: a motif module based approach for enhancer target gene prediction. Sci Rep 6:30043
Ding, Jun; Li, Xiaoman; Hu, Haiyan (2015) MicroRNA modules prefer to bind weak and unconventional target sites. Bioinformatics 31:1366-74
Miao, Ji; Ling, Alisha V; Manthena, Praveen V et al. (2015) Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun 6:6498

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