Regulation of Lipoprotein Lipase in Adipocytes

The mechanism ofLPl r~gulation is compl~, and we have:fpcused on the translatlonal regulation oflPL, which occurs in response to diabetes. and in r~sponse to hormone$$UClias thyroid hormone and epinephrine. LPLtransiationiscontrolled. by an RNA binding compre~, e'onsi$tiRg ofa member of the ~ Kinase Anchoring Protein (AKAP) family. which tethef$ PKA tospecifiecellular sites, and PKA subunits. AKAP121 contains a consensus KH RNA binding region and is a companant 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 wnich interacts with the LPL 3'UTR. This complex depends on specific sequenceetements of PKA, AKAP, and possibly other components. Aim 1. Examine AKAP14.9/121 interactions wilh 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 hyp:Qtt1yrQidjsmduetoChMge~ in AKAP expression? Aim 3. Identify LPL 3'UTR sequence elements thataiter the interaction wifh the RNA binding complex, especially tar.geting the gain of function variant known as LPLS447X Aim 4 (new), Are miRNAs involved with the translational regulation of LPL1 Hypothesis 2. By prevemingthe interaction between theRNA bfndlngcomp!ex with the LPL 3'UTR, LPL will become unresponsive to epinephrine, and adlposetissue will accumulate more lipid, diverting lipid from other insulin target organs, yielding improved insulin sensitivity, Aim 5. Examine the phenotype ota transgenic mouse that expresses LPL lacking the proxima! 3'UTR. Will this cause lipid partitioning into adipose Ussue. and improve fnsulin senSitivity? Aim 6. Examine insulin sensitivity and other phenotypic features of d.,.AKAP1 knockout mice.