Abstract 16836: Ttc39b Deficiency Attenuates Atherosclerosis and Hepatic Steatosis Through Lxrα Dependent Manner
Introduction: TTC39B was identified in genome wide association studies as a novel gene influencing HDL-cholesterol (HDL-C) levels.
Hypothesis: We assessed the hypothesis that TTC39B might have a role in LXRα target gene activation in liver or intestine.
Methods and Results: To reveal a role of TTC39B in lipid metabolism, we have investigated Ttc39b deficient mice. We found that intestinal LXRα protein, but not mRNA, were increased in chow fed Ttc39b-/- mice, leading enhancements of intestinal Abca1 mRNA and protein and HDL-C levels. 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, in addition to intestinal changes, Ttc39b-/- mice or mice with hepatocyte-specific Ttc39b deficiency showed increased hepatic LXR protein and target genes expression (Abcg5/8, Scd1, Elov5 Insig2a and Lpcat3), and these increases were reversed in Lxrα-/-Ttc39b-/- mice. 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 was decreased by 50% Ttc39b-/- mice. As a result, hepatic cholesterol and TG after eighteen weeks were dramatically decreased in Ttc39b-/- by 42 and 50% respectively. Consistently, Western Type Diet-fed Ldlr-/-Ttc39b-/- mice showed decreased fatty liver, increased HDL, decreased LDL and reduced atherosclerosis. Hepatic Abcg5/8 expression were increased and dietary cholesterol absorption were limited.
Conclusions: These studies demonstrated that Ttc39b deficiency results in increased LXRα primarily in enterocytes, beneficial lipoprotein changes and reduced atherosclerosis and hepatic lipid accumulation. Ttc39b inhibition could be an effective strategy for reducing both atherosclerosis and hepatic steatosis.
Author Disclosures: M. Koseki: None. J. Heish: None. M.M. Molusky: None. E. Yakushiji: None. M. Westerterp: None. I. Ichi: None. S. Abramowicz: None. L. Tascau: None. C.B. Welch: None. S. Takiguchi: None. J. Iqbal: None. Y. Sakata: None. S. Yamashita: None. M.M. Hussain: None. D.J. Rader: None. A.R. Tall: None.
- © 2016 by American Heart Association, Inc.