TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis
| Autor: | Shizuya Yamashita, M. Mahmood Hussain, Daniel J. Rader, Jahangir Iqbal, Marit Westerterp, Masahiro Koseki, Jay H. Lefkowitch, Alan R. Tall, Joanne Hsieh, Ikuyo Ichi, Robin B. Chan, Liana Tascau, Matthew M. Molusky, Carrie L. Welch, Sandra Abramowicz, Shunichi Takiguchi, Emi Yakushiji, Gilbert Di Paolo |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR) |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine LDL/deficiency Cholesterol Dietary/metabolism HDL/deficiency LDL/metabolism Subfamily G Cholesterol HDL/metabolism Ligands Mice chemistry.chemical_compound 0302 clinical medicine Receptors Orphan Nuclear Receptors/genetics ATP Binding Cassette Transporter Subfamily G Member 5 HDL/metabolism Liver X Receptors Lipoproteins HDL/deficiency Multidisciplinary biology Protein Stability Chemistry Fatty Acids Fatty liver Phosphatidylcholines/biosynthesis 3. Good health Cholesterol Lipogenesis/genetics 030220 oncology & carcinogenesis ABCG5 ATP Binding Cassette Transporter 1/metabolism Female lipids (amino acids peptides and proteins) medicine.medical_specialty Dietary/metabolism ATP Binding Cassette Transporter Lipoproteins Bile Acids and Salts/metabolism Lipoproteins/metabolism Diet High-Fat Member 5 Receptors LDL/deficiency Member 8 Article High cholesterol Fatty Liver/genetics 03 medical and health sciences Lipoproteins LDL/metabolism Internal medicine Unsaturated/metabolism medicine Animals Humans ATP-Binding Cassette Transporters/metabolism Liver X receptor ATP Binding Cassette Transporter Subfamily G Member 8 Sterol Regulatory Element Binding Protein 1/metabolism Ubiquitination Hepatocytes/metabolism Atherosclerosis medicine.disease Diet Fatty Acids Unsaturated/metabolism Fatty Liver High-Fat Atherosclerosis/genetics 030104 developmental biology Endocrinology Gene Expression Regulation ABCA1 Proteolysis LDL receptor biology.protein Steatohepatitis |
| Zdroj: | Nature Nature, 535:7611, 303-307. Nature Publishing Group |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature18628 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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