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 [
3
H]-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.
Dietary Free and Esterified Cholesterol Absorption in Cholesterol Esterase (Bile Salt-stimulated Lipase) Gene-targeted Mice