title: TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.
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.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koseki
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Molusky
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.affiliation: Faculty of Core Research, Ochanomizu University, Bunkyo- -ku, Tokyo 112-8610, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Ichi
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: Department of Cell Biology, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, New York 11203, USA.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Chan
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Tascau
authors.affiliation: 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.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Department of Cell Biology, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, New York 11203, USA.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy; D001647:Bile Acids and Salts / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D059305:Diet, High-Fat; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D008024:Ligands; D050155:Lipogenesis / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010713:Phosphatidylcholines; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; C577833:Abca1 protein, mouse; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C000609737:TTC39B protein, mouse