Abstract

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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Acknowledgements

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.).

Author information

Author notes

    • Joanne Hsieh
    •  & Masahiro Koseki

    These authors contributed equally to this work.

Affiliations

  1. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA

    • Joanne Hsieh
    • , Masahiro Koseki
    • , Matthew M. Molusky
    • , Emi Yakushiji
    • , Marit Westerterp
    • , Sandra Abramowicz
    • , Liana Tascau
    • , Carrie L. Welch
    •  & Alan R. Tall
  2. Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

    • Masahiro Koseki
    •  & Shizuya Yamashita
  3. Faculty of Core Research, Ochanomizu University, Bunkyoˉ -ku, Tokyo 112-8610, Japan

    • Ikuyo Ichi
  4. Department of Cell Biology, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, New York 11203, USA

    • Jahangir Iqbal
    •  & M. Mahmood Hussain
  5. Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA

    • Robin B. Chan
    • , Gilbert Di Paolo
    •  & Jay H. Lefkowitch
  6. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA

    • Shunichi Takiguchi
    •  & Daniel J. Rader
  7. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA

    • Shunichi Takiguchi
    •  & Daniel J. Rader

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Contributions

J.H. and M.K. generated epitope-tagged constructs, bred mice, performed in vivo and cell culture experiments, collected data, designed the study, interpreted data, and wrote the paper; M.M.M. isolated hepatocytes and performed the chromatin immunoprecipitation and insulin sensitivity experiments; E.Y. and L.T. collected data; I.I. performed oxysterol and plant sterol measurements; M.W., S.A. and C.B.W. performed atherosclerotic lesion analysis; R.B.C and G.D. designed and performed lipidomics analyses; J.I. performed enterocyte ex vivo secretion studies; S.T. performed microarray analysis; J.H.L. performed histopathological analyses of liver sections; D.J.R., M.M.H., and S.Y. were involved in study design; A.R.T. designed the study, interpreted data, and wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Masahiro Koseki or Alan R. Tall.

Reviewer Information Nature thanks C. Semenkovich, A. von Eckardstein and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains the uncropped blots from the Main and Extended Data Figures.

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DOI

https://doi.org/10.1038/nature18628

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