The mechanism of LPL regulation is complex, and we have focused on the translational regulation of LPL, which occurs in response to diabetes, and in response to hormones such as thyroid hormone and epinephrine. LPL translation is controlled by an RNA binding complex, consisting of a member of the A-Kinase Anchoring Protein (AKAP) family, which tethers PKA to specific cellular sites, and PKA subunits. AKAP121 contains a consensus KH RNA binding region and is a component of the RNA binding complex. Therefore, we plan to examine LPL translation regulation by studying both the RNA binding complex, and the LPL mRNA. Hypothesis 1. LPL translation is regulated by an RNA binding complex which interacts with the LPL 3'UTR. This complex depends on specific sequence elements of PKA, AKAP, and possibly other components.
Aim 1. Examine AKAP149/121 interactions with other elements of the PKA complex, and examine the interactions between PKA and PKC with regards to LPL regulation.
Aim 2. Is the increase in LPL translation from hypothyroidism due to changes in AKAP expression? Aim 3. Identify LPL 3'UTR sequence elements that alterthe interaction with the RNA binding complex, especially targeting the gain of function variant Known as LPLS447X:
Aim 4 (new). Are miRNAs involved with the translational regulation of LPL? Hypothesis 2. By preventing the interaction between the RNA binding complex with the LPL 3'UTR, LPL will become unresponsive to epinephrine, and adipose tissue will accumulate more lipid, diverting lipid from other insulin target organs, yielding improved insulin sensitivity.
Aim 5. Examine the phenotype of a transgenic mouse that expresses LPL lacking the proximal 3'UTR. Will this cause lipid partitioning into adipose tissue, and improve insulin sensitivity? Aim 6. Examine insulin sensitivity and other phehotypic feaitures ofid-AKAPI knocl<out mice.

Public Health Relevance

Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism. LPL is synthesized and secreted by adipocytes and muscle cells and hydrolyzes the triglyceride core of circulating VLDL and chylomicrons. Abnormalities in LPL are important in atherosclerosis and diabetes, where the inefficient catabolism of triglyceride rich lipoproteins leads to the formation of highly atherogenic remnant lipoproteins.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Haft, Carol R
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University of Kentucky
Internal Medicine/Medicine
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