Journal of Stem Cell Research & Therapy

A TGFβLRP1/Wnt5a pathway protects against intracellular cholesterol accumulation through inhibition of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity, and increased cholesterol efflux

3^rd International Conference and Exhibition on Cell & Gene Therapy

October 27-29, 2014 Embassy Suites Las Vegas, USA

Philippe Boucher, Zeina El Asmar, Marion Jenty, Lionel Host, V?ronique Bruban, J?rome Terrand, Rachel L Matz, Russel A DeBose-Boyd and Joachim Herz

Accepted Abstracts: J Stem Cell Res Ther

Abstract:

Adipose tissue is an easily accessible tissue that in addition to its roles in storage of excess energy in form of triglyceride also contains the largest pool of cholesterol in the body and plays a critical role in maintaining cholesterol homeostasis. The mechanism of this regulation is however unknown. We reported previously that LRP1, a trans-membrane receptor positively regulates a Wnt5a signaling pathway that protects against intracellular cholesterol and cholesteryl-esters accumulation in cells submitted to adipogenesis. To investigate the role of Wnt5a in cholesterol homeostasis mice overexpressing Wnt5a in adipose tissue (aTgWnt5a) was generated. aTgWnt5a mice fed a regular chow diet exhibit a decrease in adipocyte cholesterol levels with no difference in triglycerides content compared to controls. This was accompanied by an inhibition in adipose tissue of the HMG-CoA reductase, the rate-limiting enzyme for cholesterol biosynthesis. mRNA and protein levels of HMG CoA reductase were both severely decreased compared to controls suggesting that Wnt5a interfere with cholesterol biosynthesis. In agreement with this hypothesis, an increase in Insig-1 protein and mRNA levels in adipocytes from these mice was found, with no difference in SREBPs mRNA expressions. In vitro effects of Wnt5a on the HMGCoA reductase levels were confirmed. Similarly, Wnt5a increased Insig-1 protein when stably transfected in MEFs. In agreement with an inhibition effect of Wnt5a on cholesterol biosynthesis, SREBP2 cleavage, and nuclear translocation were reduced in Wnt5a transfected cells. These data suggested that Wnt5a protects against cholesterol intracellular accumulation through inhibition of its biosynthesis.

Biography :

Philippe Boucher is Professor of Physiology at University of Strasbourg. After a PhD at the University of Lyon, France and a Postdoctoral fellowship at UT Southwestern Medical Center at Dallas he became an Assistant Professor of Physiology at University of Strasbourg before moving on as a full Professor position. His lab aims to understand cell-signalling networks and, in more specific terms, how LRP1 and its partners impact on growth-promoting and differentiation signals that protect against disorders such as atherosclerosis and obesity. He has published more than 25 papers in reputed journals. His work has identified several fundamental molecular mechanisms by which these genes protect against atherosclerosis, heart failure, and maintain cholesterol homeostasis..