Ttc39b Deficiency Causes an Intestinal Lxr Activation Phenotype with Increased Expression of Abca1 and Hdl-Cholesterol Levels

TTC39B (T39) was identified in a GWAS as a novel gene influencing HDL cholesterol (HDL-c) levels. We have now verified increased HDL-c levels in T39-/- mice. On a chow diet HDL-c levels were significantly increased by 22% and there were increases in LXR protein but not mRNA, increased expression of ABCA1 mRNA and protein and increased secretion of HDL by small intestinal enterocytes. When mice were challenged with a high fat/high cholesterol/bile salt (Paigen) diet, there was a significant 42% increase in HDL-c and also decreased incorporation of dietary cholesterol and fat into chylomicrons and marked protection from steato-hepatitis; in addition to intestinal changes, there was increased LXR protein and induction of Abcg5/8 in liver. Ldlr-/-T39-/- mice on the Western diet showed increased HDL-c, decreased V/LDL cholesterol and decreased atherosclerosis. These studies show that T39 deficiency results in increased LXR primarily in enterocytes, beneficial lipoprotein changes and reduced atherosclerosis. Moreover, T39-/- mice are protected from fatty liver, indicating that T39 inhibition could be an effective strategy for reducing atherosclerosis and fatty liver.