Journal Article

TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis

Takiguchi, Shunichi, Koseki, Masahiro, Yakushiji, Emi, Iqbal, Jahangir, Molusky, Matthew M., Tascau, Liana, Di Paolo, Gilbert, Rader, Daniel J., Ichi, Ikuyo, Tall, Alan R., Lefkowitch, Jay H., Abramowicz, Sandra, Yamashita, Shizuya, Welch, Carrie L., Hussain, M. Mahmood, Hsieh, Joanne, Chan, Robin B., Westerterp, Marit

2016

Overview

In mice, deficiency in the high-density lipoprotein gene T39 stabilizes liver X receptor (LXR), reducing both atherosclerosis and steatohepatitis, suggesting that T39 inhibition could be an effective strategy for reducing these diseases. Anti-atherosclerosic and anti-steatohepatitic Genome-wide association studies have shown that single-nucleotide polymorphisms in the T39 gene, coding for the tetratricopeptide repeat protein 39B, are associated with increased high-density lipoprotein cholesterol levels. Here, Alan Tall and colleagues show in mice that T39 deficiency protects against atherosclerosis through a mechanism that involves stabilization of LXR, a known anti-atherogenic transcription factor. Unlike synthetic LXR ligands, however, T39 deficiency also protects against fatty liver, suggesting that T39 inhibition could be a therapeutic approach to both cardiovascular disease and non-alcoholic fatty liver disease. Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available 1 , are poorly understood. Despite the fact that 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. Here we show that tetratricopeptide repeat domain protein 39B ( Ttc39b , C9orf52) ( T39 ), a high-density lipoprotein gene discovered in human genome-wide association studies 2 , promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 ( T39 −/− ) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 ( Abca1 ) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39 −/− mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor ( Ldlr −/− T39 −/− ) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids 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 steatohepatitis and atherosclerosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/319/1642 / 631/45/287 / 64 / 64/60 / 82 / Animals / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - prevention & control / Atherosclerosis - therapy / ATP Binding Cassette Transporter 1 - metabolism / ATP Binding Cassette Transporter, Sub-Family G, Member 5 / ATP Binding Cassette Transporter, Sub-Family G, Member 8 / ATP-Binding Cassette Transporters - metabolism / Bile Acids and Salts - metabolism / Biosynthesis / Blood lipoproteins / Cholesterol / Cholesterol, Dietary - metabolism / Cholesterol, HDL - metabolism / Diet / Diet, High-Fat / Fatty Acids, Unsaturated - metabolism / Fatty Liver - genetics / Fatty Liver - prevention & control / Fatty Liver - therapy / Female / Gene expression / Gene Expression Regulation / Genetic aspects / Health aspects / Hepatocytes - metabolism / Humanities and Social Sciences / letter / Ligands / Lipogenesis - genetics / Lipoproteins / Lipoproteins - metabolism / Lipoproteins, HDL - deficiency / Lipoproteins, HDL - genetics / Lipoproteins, HDL - metabolism / Lipoproteins, LDL - metabolism / Liver / Liver diseases / Liver X Receptors / Male / Mice / multidisciplinary / Orphan Nuclear Receptors - genetics / Orphan Nuclear Receptors - metabolism / Phosphatidylcholines - biosynthesis / Phosphatidylcholines - metabolism / Polyunsaturated fatty acids / Properties / Protein Stability / Proteins / Proteolipids / Proteolysis / Receptors, LDL - deficiency / Receptors, LDL - genetics / Risk factors / Science / Sterol Regulatory Element Binding Protein 1 - metabolism / Transcription factors / Ubiquitin-proteasome system / Ubiquitination