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Pharmacologic inhibition of phospholipid transfer protein activity reduces apolipoprotein-B secretion from hepatocytes. | LitMetric

Pharmacologic inhibition of phospholipid transfer protein activity reduces apolipoprotein-B secretion from hepatocytes.

J Pharmacol Exp Ther

Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research Division, Pfizer Inc., Groton, CT 06340, USA.

Published: March 2010

Phospholipid transfer protein (PLTP) plays an important role in atherogenesis, and its function goes well beyond that of transferring phospholipids between lipoprotein particles. Previous studies showed that genetic deficiency of PLTP in mice causes a substantially impaired hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins. To understand whether the impaired apoB secretion is a direct result from lack of PLTP activity, in this study, we further investigated the function of PLTP in apoB secretion by using PLTP inhibitors. We identified a series of compounds containing a 3-benzazepine core structure that inhibit PLTP activity. Compound A, the most potent inhibitor, was characterized further and had little cross-reactivity with microsomal triglyceride transfer protein. Compound A reduced apoB secretion in human hepatoma cell lines and mouse primary hepatocytes. Furthermore, we confirmed that the reduction of apoB secretion mediated by compound A is PLTP-dependent, because the PLTP inhibitor had no effect on apoB secretion from PLTP-deficient hepatocytes. These studies provided evidence that PLTP activity regulates apoB secretion and pharmacologic inhibition of PLTP may be a new therapy for dyslipidemia by reducing apoB secretion.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835446PMC
http://dx.doi.org/10.1124/jpet.109.161232DOI Listing

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