Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available1, 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 studies2, 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.
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We express our gratitude to F. Matsuura for support, A. Morishita for advice on liver histology, M. Sakurai and T. Yamashita for advice on immunoprecipitation experiments, W. R. Lagor for advice on the reverse cholesterol transport study, M. Ishibashi for advice on animal administration, J. W. Medley for consultation on the coupling reaction, and N. Wang for project discussions. D. J. Gorman and J. So provided technical support, and O. Xu provided technical services for the lipidomics analysis. This work was supported by grants from the Manpei Suzuki Diabetes Foundation (to M.K.), VIDI grant 91715350 from the Netherlands Organization of Sciences (to M.W.), Rosalind Franklin Fellowship from the University Medical Center Groningen (to M.W.), JSPS KAKENHI Grant 15K160203 (to I.I.), and the Fondation Leducq (to A.R.T.). This work was supported by grants from the National Institutes of Health (T32 training program HL007343, M.M.M.; HL087123 and HL119830, to A.R.T.; HL101864 and HL111398, to D.J.R.; DK46900, to M.M.H.).
Extended data figures
This file contains the uncropped blots from the Main and Extended Data Figures.
About this article
Current Cardiology Reports (2017)