Question

PLEASE Help ASAP!!

1. Some patients being treated for cardiovascular disease are partially resistant to statin drugs and have LDL levels that are still unacceptably high. Treatment with ETC-1002 has been shown to be a good alternative as serum LDL levels can be significantly decreased in these patients (Esperion stock prices rose 19% on this news). However, one must be concerned about safety and tolerability of new drugs and tests need to be conducted. What were the major safety and tolerability concerns regarding the use of ETC-1002 that were identified in a double blind placebo controlled study using 56 patients with a history of statin resistance?

2. The drug ETC-1002 has a dual function that inhibits citrate lyase activity and activates AMPK activity. a) What is a key enzyme in the fatty acid synthesis pathway that is regulated by AMPK, and what is the biochemical mechanism of this regulation, i.e., how does AMPK regulate the activity of this enzyme? Why does regulation of this enzyme by AMPK lead to decreased serum LDL? b) AMPK phosphorylates transcription factors and regulates their activity. What two downstream transcriptional effects are mediated by activated AMPK, and why would this lead to decreased serum LDL.

Answer 1

1. Key enzyme in the fatty acid synthesis pathway that is regulated by AMPK is Acetyl CoA Carboxylase (ACC).

AMPK phosphorylates ACC1 @ ser 79 leading to decreased fatty acid synthesis. Hence Melonyl CoA synthesis is reduced. Thereby decreasing fatty acids. Also AMPK phosphorylates HMG CoA reductase and deactivates it leading to decreased cholesterol sysnthesis. Also AMPK regulate fatty acid oxidation by phosphorylation of transcription factors such as CREB & PGC- 1alpha. The c AMP - responsive transcription factor CREB activates glucogenic and fatty acid oxidation programmes by stimulating expression of nuclear hormone receptor coactivator PGC - 1 . increased Fatty acid oxidation leading to decreased Serum LDL.