Abstract

(Scanned from the Applicant's Description): Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism and adipocyte biology. Although the changes in LPL activity with diabetes and other conditions have been well described, the mechanism of LPL regulation is complex. We have described regulation of LPL translation in response to catecholamines, thyroid hormone, and in diabetes. Our recent studies have described an RNA binding protein that inhibited translation through binding to the 3'UTR of the LPL mRNA. We have now identified a member of the RNA binding complex as the alpha catalytic subunit of cAMP dependent protein kinase (PKA). In addition, we have produced transgenic mice that express an LPL gene (LPLt) that lacks the RNA binding motif on the 3'UTR. Our future aims are to better characterize the role of PKA in LPL regulation, and to better understand the role of translation in the physiologic regulation of LPL. Hypothesis 1. Protein kinase A (PKA) is involved in the translational regulation of LPL.
Aim 1. Characterize the binding of the PKA C subunit to LPL mRNA: tissue specificity and involvement of other proteins.
Aim 2. Determine the sequence and kinase activity of the C subunit involved in translational regulation.
Aim 3. Characterize the motif on the 3'UTR of LPL that is involved in C binding.
Aim 4. Determine whether LPL translation is altered in PKA knockout mice. Hypothesis 2. Regulation of LPL translation is important physiologically.
Aim 1. Examine the translational regulation of both LPLt and wild type LPL (LPLwt) in response to epinephrine, thyroid hormone, and phorbol ester in isolated adipocytes from transgenic mice.
Aim 2. Examine the regulation of LPLt and LPLwt in adipose tissue of transgenic mice following the induction of streptozotocin-diabetes or hypothyroidism, and the in vivo administration of epinephrine.
Aim 3. Examine the mechanism by which the expression of LPLt in transgenic mice is accompanied by a down regulation of wild type LPL.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK039176-16
Application #
6761785
Study Section
Special Emphasis Panel (ZRG1-SSS-T (01))
Program Officer
Haft, Carol R
Project Start
1988-09-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
16
Fiscal Year
2004
Total Cost
$279,000
Indirect Cost

  Institution

Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205

  Publications

Ye, Ruisong; Pi, Min; Cox, John V et al. (2017) CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. J Exp Clin Cancer Res 36:90
Walton, R Grace; Zhu, Beibei; Unal, Resat et al. (2015) Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity. J Biol Chem 290:11547-56
Yao-Borengasser, Aiwei; Varma, Vijayalakshmi; Coker, Robert H et al. (2011) Adipose triglyceride lipase expression in human adipose tissue and muscle. Role in insulin resistance and response to training and pioglitazone. Metabolism 60:1012-20
Zhang, Haihong; Xie, Chenghui; Spencer, Horace J et al. (2011) Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. Am J Pathol 178:1715-27
Unal, Resat; Yao-Borengasser, Aiwei; Varma, Vijayalakshmi et al. (2010) Matrix metalloproteinase-9 is increased in obese subjects and decreases in response to pioglitazone. J Clin Endocrinol Metab 95:2993-3001
Spencer, Michael; Yao-Borengasser, Aiwei; Unal, Resat et al. (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016-27
Rasouli, Neda; Yao-Borengasser, Aiwei; Varma, Vijayalakshmi et al. (2009) Association of scavenger receptors in adipose tissue with insulin resistance in nondiabetic humans. Arterioscler Thromb Vasc Biol 29:1328-35
Varma, Vijayalakshmi; Yao-Borengasser, Aiwei; Rasouli, Neda et al. (2009) Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action. Am J Physiol Endocrinol Metab 296:E1300-10
Banga, Anannya; Unal, Resat; Tripathi, Preeti et al. (2009) Adiponectin translation is increased by the PPARgamma agonists pioglitazone and omega-3 fatty acids. Am J Physiol Endocrinol Metab 296:E480-9
Unal, Resat; Pokrovskaya, Irina; Tripathi, Preeti et al. (2008) Translational regulation of lipoprotein lipase in adipocytes: depletion of cellular protein kinase Calpha activates binding of the C subunit of protein kinase A to the 3'-untranslated region of the lipoprotein lipase mRNA. Biochem J 413:315-22

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