TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis

Cellular mechanisms that mediate steato-hepatitis, an increasingly prevalent condition in the Western world for which no therapies are available(1), are poorly understood. Despite the fact its synthetic agonists induce fatty liver, the Liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal and anti-inflammatory activities. We discovered that tetratricopeptide repeat (TPR) domain protein 39B (Ttc39b, C9orf52) (T39), a high density lipoprotein (HDL) gene discovered in human genome wide association studies (GWAS)(2), promotes the ubiquitination and degradation of LXR. Chow-fed T39(-/-) mice displayed increased HDL cholesterol levels associated with increased enterocyte ATP binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR mRNA. When challenged with a high fat/high cholesterol/bile salt (HF/HC/BS) diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency showed increased hepatic LXR protein and target gene expression, and unexpectedly protection from steato-hepatitis and death. Western Type Diet (WTD)-fed Low density lipoprotein receptor (Ldlr)(-/-)T39(-/-) mice showed decreased fatty liver, increased HDL, decreased LDL and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibited hepatic sterol regulatory element binding protein 1 (SREBP-1, ADD1) processing. This was explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids (PUFA), linked to an LXRα-dependent increase in expression of enzymes mediating PC biosynthesis and incorporation of PUFA into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steato-hepatitis and atherosclerosis.