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TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.
Nature. 2016 07 14; 535(7611):303-7.Nat

Abstract

Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, 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, 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.

Authors+Show Affiliations

Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA. Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Faculty of Core Research, Ochanomizu University, Bunkyo- -ku, Tokyo 112-8610, Japan.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Department of Cell Biology, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, New York 11203, USA.Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.Department of Cell Biology, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, New York 11203, USA.Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27383786

Citation

Hsieh, Joanne, et al. "TTC39B Deficiency Stabilizes LXR Reducing Both Atherosclerosis and Steatohepatitis." Nature, vol. 535, no. 7611, 2016, pp. 303-7.
Hsieh J, Koseki M, Molusky MM, et al. TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature. 2016;535(7611):303-7.
Hsieh, J., Koseki, M., Molusky, M. M., Yakushiji, E., Ichi, I., Westerterp, M., Iqbal, J., Chan, R. B., Abramowicz, S., Tascau, L., Takiguchi, S., Yamashita, S., Welch, C. L., Di Paolo, G., Hussain, M. M., Lefkowitch, J. H., Rader, D. J., & Tall, A. R. (2016). TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature, 535(7611), 303-7. https://doi.org/10.1038/nature18628
Hsieh J, et al. TTC39B Deficiency Stabilizes LXR Reducing Both Atherosclerosis and Steatohepatitis. Nature. 2016 07 14;535(7611):303-7. PubMed PMID: 27383786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. AU - Hsieh,Joanne, AU - Koseki,Masahiro, AU - Molusky,Matthew M, AU - Yakushiji,Emi, AU - Ichi,Ikuyo, AU - Westerterp,Marit, AU - Iqbal,Jahangir, AU - Chan,Robin B, AU - Abramowicz,Sandra, AU - Tascau,Liana, AU - Takiguchi,Shunichi, AU - Yamashita,Shizuya, AU - Welch,Carrie L, AU - Di Paolo,Gilbert, AU - Hussain,M Mahmood, AU - Lefkowitch,Jay H, AU - Rader,Daniel J, AU - Tall,Alan R, Y1 - 2016/07/06/ PY - 2013/12/16/received PY - 2016/06/02/accepted PY - 2016/7/8/entrez PY - 2016/7/8/pubmed PY - 2016/8/16/medline SP - 303 EP - 7 JF - Nature JO - Nature VL - 535 IS - 7611 N2 - Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, 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, 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/27383786/TTC39B_deficiency_stabilizes_LXR_reducing_both_atherosclerosis_and_steatohepatitis_ L2 - https://doi.org/10.1038/nature18628 DB - PRIME DP - Unbound Medicine ER -