TMEM135 is an LXR-inducible regulator of peroxisomal metabolism

Abstract

Summary 24The liver x receptors (LXRs) are key regulators of systemic lipid metabolism. We identified 25 transmembrane protein 135 (TMEM135), a peroxisomal protein with an unknown function, as a 26 novel LXR target gene. The LXRs directly induce TMEM135 transcription in humans via an LXR 27 response element in the 5' untranslated region, but do not increase Tmem135 in murine cells. 28Functionally, knockdown of TMEM135 in vitro and in vivo results in many features typical of 29 peroxisomal disorders such as steatosis and reduced peroxisomal β-oxidation. Mechanistically, 30 proteomic and Western blot analyses indicated that TMEM135 mediates import of peroxisome 31 matrix proteins necessary for β-oxidation and bile acid synthesis. These findings indicate that 32 TMEM135 is an LXR-inducible regulator of peroxisome catabolic and anabolic processes by 33 mediating an auxiliary matrix protein import pathway, and thus may represent a novel therapeutic 34 target for disorders associated with peroxisome dysfunction. 35 Introduction 36The liver x receptors (LXR) α (NR1H3) and β (NR1H2) belong to the nuclear receptor 37 superfamily and are key regulators of cholesterol and fatty acid metabolism (1). Natural LXR 38 ligands include oxysterols (2) that increase during cholesterol loading and activate LXR-mediated 39 transcription. The LXRs heterodimerize with the retinoic acid receptor (RXR) and bind to LXR 40 response elements (LXRE) within the promoters of target genes (2). The LXREs belong to the 41 direct repeat 4 (DR4) class that consist of two hexanucleotide half-sites separated by a 4-42 nucleotide spacer (3,4). The protein products of known LXR target genes affect systemic lipid 43 metabolism. Well known examples include increasing cholesterol efflux via ATP-binding cassette 44 (ABC) sub-family A, member 1 (ABCA1) (5), and sub-family G, member 1 (ABCG1) (6); limiting 45 cholesterol uptake via induction of myosin regulatory light chain interacting protein (MYLIP) that 46 targets the low-density lipoprotein receptor (LDLR) for ubiquitin-mediated degradation (7); and 47 increased lipogenesis via induction of sterol regulatory element binding protein 1c (SREBP1c, 48 encoded by sterol regulatory element binding transcription factor 1 gene or SREBF1) (8,9). Also, 49. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/334979 doi: bioRxiv preprint first posted online May. 30, 2018; 3 the NR1H3 isoform of the LXRs is itself an LXR target gene (10,11), leading to auto-amplification 50 of LXR actions in certain species and tissues. Although many LXR target genes have been 51 discovered, additional target genes may remain unidentified. 52We have previously investigated LXR actions within the steroidogenic corpus luteum of 53 the ovary (12)(13)(14). In an attempt to uncover novel LXR target genes, rhesus macaque luteal cells ...

Leveraging functional annotation to identify genes associated with complex diseases

“…The associated gene identified at the other novel locus, TMEM135 (p = 1.80e-8) is located 1MB ( Fig 6 ) downstream of the identified GWAS locus (the PICALM locus), and two of the identified eQTLs of TMEM135 by our method were located at the GWAS loci (rs536841: p = 5.27e-14 and rs541458: p = 5.67e-12). On the other hand, TMEM135 is a target gene for liver X receptors (LXR), which is involved in removing excessive cholesterol from peripheral tissues [ 53 ]. Increased cholesterol levels in brain tissue are associated with accumulated AβPP [ 51 ] suggesting the potential role of LXR and TMEM135 in the etiology of AD.…”

Peroxisomal Metabolite and Cofactor Transport in Humans

“…In PMP52 knockdown mice a few peroxisomal matrix proteins – ACAA1 and SCP2 – were mislocalized to the cytosol which suggests a role of PMP52 in peroxisomal matrix protein import ( Renquist et al, 2018 ). In the same study, an increased level of triglycerides was found in HepG2 cells with a knockdown of PMP52 ( Renquist et al, 2018 ).…”

“…In PMP52 knockdown mice a few peroxisomal matrix proteins – ACAA1 and SCP2 – were mislocalized to the cytosol which suggests a role of PMP52 in peroxisomal matrix protein import ( Renquist et al, 2018 ). In the same study, an increased level of triglycerides was found in HepG2 cells with a knockdown of PMP52 ( Renquist et al, 2018 ). Finally, in two different mouse models in which either very long-chain acyl-CoA dehydrogenase (VLCAD) or long-chain acyl-CoA dehydrogenase (LCAD) were disrupted, PMP52 levels were significantly elevated.…”

TMEM135 is a Novel Regulator of Mitochondrial Dynamics and Physiology with Implications for Human Health Conditions

“…Mitochondria and peroxisomes both oxidize LCFAs (C14–C18), whereas only peroxisomes oxidize very-long-chain fatty acids (VLCFAs, >C20) [ 54 ]. Renquist et al used electrophoretic mobility shift assay (EMSA) and chromatic immunoprecipitation (ChIP) analysis to demonstrate that the human TMEM135 promoter contains a liver X receptor (LXR) response element that binds LXRs and mediates LXR-induced transcription [ 12 , 55 ]. This response element was notably not found in murine cells [ 56 ].…”

“…Consistent with increased fatty acid uptake and beta-oxidation, fasting augmented hepatic fatty acid and NADH concentrations in control mice. Compared with the control mice, fasted TMEM135-knockdown mice displayed a further increase in hepatic fatty acid concentrations and a significant decrease in NADH concentration, suggesting impairment of peroxisomal beta-oxidation [ 55 ]. The peroxisomal contribution to overall LCFA beta-oxidation becomes greater during physiological states of increased fatty acid load, such as fasting, which might partly explain why TMEM135 protein levels were increased in heart and skeletal muscle during fasting and cold stress in mice [ 1 ].…”