Abstract 20416: Ttc39b Deficiency Has a Beneficial Role on Cholesterol and Triglyceride Absorption in Enterocytes
Background: TTC39B, encoding tetratricopeptide repeat domain 39B, was identified in genome wide association studies (GWAS) as a novel gene influencing HDL-cholesterol (HDL-C) levels. Since Ttc39b had not been previously implicated in lipoprotein metabolism at all and nothing was known about the functions of Ttc39b, we investigated animal models.
Method and Results: We have found that on a chow diet there were increases in LXR protein but not mRNA, increased expression of Abca1 mRNA and protein and 22% increased HDL-C levels in Ttc39b-/- mice.
Experiments using primary enterocytes isolated from Ttc39b-/- mice revealed that secretion of particles containing apoA-1 increased by approximately twofold. When mice were fed with a high fat/high cholesterol/bile salt diet, primary enterocytes secreted 50% less particles not containing apoA-1, as well as particles containing apoA-1 by twofold. In the cholesterol absorption study by gavaging [3H]-cholesterol total cholesterol absorption were decreased by 50% Ttc39b-/- mice. As a result, hepatic cholesterol and TG after mice were fed with a high fat/high cholesterol/bile salt diet for eighteen week were dramatically decreased in Ttc39b-/- by 42 and 50% respectively. In addition, external oxysterols, such as 7b-hydroxycholesterol and 7-ketocholesterol were also parallel decreased.
Conclusion: These studies show that Ttc39b deficiency results in increased LXR primarily in enterocytes, beneficial lipoprotein changes and reduced atherosclerosis. Moreover, Ttc39b-/- mice were protected from fatty liver, indicating that Ttc39b inhibition could be an effective strategy for reducing atherosclerosis and fatty liver.
Author Disclosures: M. Koseki: None. J. Hsieh: None. E. Yakushiji: None. C. Welch: None. J. Iqbal: None. M.M. Hussain: None. A.R. Tall: None. Y. Sakata: None. S. Yamashita: None.
- © 2014 by American Heart Association, Inc.