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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947007/ https://www.ncbi.nlm.nih.gov/pubmed/27383786 http://dx.doi.org/10.1038/nature18628 |
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author | Hsieh, Joanne Koseki, Masahiro Molusky, Matthew M. Yakushiji, Emi Ichi, Ikuyo Westerterp, Marit Iqbal, Jahangir Chan, Robin B. Abramowicz, Sandra Tascau, Liana Takiguchi, Shunichi Yamashita, Shizuya Welch, Carrie L. Di Paolo, Gilbert Hussain, M. Mahmood Lefkowitch, Jay H. Rader, Daniel J. Tall, Alan R. |
author_facet | Hsieh, Joanne Koseki, Masahiro Molusky, Matthew M. Yakushiji, Emi Ichi, Ikuyo Westerterp, Marit Iqbal, Jahangir Chan, Robin B. Abramowicz, Sandra Tascau, Liana Takiguchi, Shunichi Yamashita, Shizuya Welch, Carrie L. Di Paolo, Gilbert Hussain, M. Mahmood Lefkowitch, Jay H. Rader, Daniel J. Tall, Alan R. |
author_sort | Hsieh, Joanne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4947007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-49470072017-01-14 TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis Hsieh, Joanne Koseki, Masahiro Molusky, Matthew M. Yakushiji, Emi Ichi, Ikuyo Westerterp, Marit Iqbal, Jahangir Chan, Robin B. Abramowicz, Sandra Tascau, Liana Takiguchi, Shunichi Yamashita, Shizuya Welch, Carrie L. Di Paolo, Gilbert Hussain, M. Mahmood Lefkowitch, Jay H. Rader, Daniel J. Tall, Alan R. Nature Article 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. 2016-07-14 /pmc/articles/PMC4947007/ /pubmed/27383786 http://dx.doi.org/10.1038/nature18628 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hsieh, Joanne Koseki, Masahiro Molusky, Matthew M. Yakushiji, Emi Ichi, Ikuyo Westerterp, Marit Iqbal, Jahangir Chan, Robin B. Abramowicz, Sandra Tascau, Liana Takiguchi, Shunichi Yamashita, Shizuya Welch, Carrie L. Di Paolo, Gilbert Hussain, M. Mahmood Lefkowitch, Jay H. Rader, Daniel J. Tall, Alan R. TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title | TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title_full | TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title_fullStr | TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title_full_unstemmed | TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title_short | TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis |
title_sort | ttc39b deficiency stabilizes lxr reducing both atherosclerosis and steatohepatitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947007/ https://www.ncbi.nlm.nih.gov/pubmed/27383786 http://dx.doi.org/10.1038/nature18628 |
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