Liver X receptor alpha explained

Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene (nuclear receptor subfamily 1, group H, member 3).^{[1] [2]}

Expression

miRNA hsa-miR-613 autoregulates the human LXRα gene by targeting the endogenous LXRα through its specific miRNA response element (613MRE) within the LXRα 3′-untranslated region. LXRα autoregulates its own suppression via induction of SREBP1c which upregulates miRNA has-miR-613.^[3]

Function

The liver X receptors, LXRα (this protein) and LXRβ, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. Additionally, they play an important role in the local activation of thyroid hormones via deiodinases.^[4] The inducible LXRα is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRβ is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs) and regulate expression of target genes containing LXR response elements.^{[5] [6]} Restoration of LXR-alpha expression/function within a psoriatic lesion may help to switch the transition from psoriatic to symptomless skin.^[7]

Interactions

Liver X receptor alpha has been shown to interact with EDF1^[8] and small heterodimer partner.^[9] LXRα activates the transcription factor SREBP-1c, resulting in lipogenesis.^[10]

Link to multiple sclerosis

In 2016, a study found 70% of individuals in two families with a rare form of rapidly progressing multiple sclerosis had a mutation in NR1H3.^[11] However, an analysis from The International Multiple Sclerosis Genetics Consortium using a 13-fold larger sample size could not find any evidence that the mutation in question (p.Arg415Gln) associated with multiple sclerosis, refuting these findings.^[12]

Further reading

• Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM . Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway . The Journal of Biological Chemistry . 272 . 6 . 3137–40 . Feb 1997 . 9013544 . 10.1074/jbc.272.6.3137 . free .
• Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, Staels B, Auwerx J, Laville M, Vidal H . Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients . Diabetes . 46 . 8 . 1319–27 . Aug 1997 . 9231657 . 10.2337/diabetes.46.8.1319 .
• Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ . Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha . Cell . 93 . 5 . 693–704 . May 1998 . 9630215 . 10.1016/S0092-8674(00)81432-4 . 5856580 . free .
• Miyata KS, McCaw SE, Meertens LM, Patel HV, Rachubinski RA, Capone JP . Receptor-interacting protein 140 interacts with and inhibits transactivation by, peroxisome proliferator-activated receptor alpha and liver-X-receptor alpha . Molecular and Cellular Endocrinology . 146 . 1–2 . 69–76 . Nov 1998 . 10022764 . 10.1016/S0303-7207(98)00196-8 . 53253694 .
• Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P . Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha . Proceedings of the National Academy of Sciences of the United States of America . 97 . 22 . 12097–102 . Oct 2000 . 11035776 . 17300 . 10.1073/pnas.200367697 . 2000PNAS...9712097V . free .
• Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B . PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway . Nature Medicine . 7 . 1 . 53–8 . Jan 2001 . 11135616 . 10.1038/83348 . 20558311 .
• Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P . LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes . Proceedings of the National Academy of Sciences of the United States of America . 98 . 2 . 507–12 . Jan 2001 . 11149950 . 14617 . 10.1073/pnas.021488798 . free .
• Li Y, Bolten C, Bhat BG, Woodring-Dietz J, Li S, Prayaga SK, Xia C, Lala DS . Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism . Molecular Endocrinology . 16 . 3 . 506–14 . Mar 2002 . 10.1210/mend.16.3.0789 . 11875109 . free .
• Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P, Edwards PA . Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta . The Journal of Biological Chemistry . 277 . 35 . 31900–8 . Aug 2002 . 12032151 . 10.1074/jbc.M202993200 . free .
• Brendel C, Gelman L, Auwerx J . Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism . Molecular Endocrinology . 16 . 6 . 1367–77 . Jun 2002 . 12040021 . 10.1210/mend.16.6.0843 . free .
• Steffensen KR, Schuster GU, Parini P, Holter E, Sadek CM, Cassel T, Eskild W, Gustafsson JA . Different regulation of the LXRalpha promoter activity by isoforms of CCAAT/enhancer-binding proteins . Biochemical and Biophysical Research Communications . 293 . 5 . 1333–40 . May 2002 . 12054659 . 10.1016/S0006-291X(02)00390-X .
• Gbaguidi GF, Agellon LB . The atypical interaction of peroxisome proliferator-activated receptor alpha with liver X receptor alpha antagonizes the stimulatory effect of their respective ligands on the murine cholesterol 7alpha-hydroxylase gene promoter . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1583 . 2 . 229–36 . Jul 2002 . 12117567 . 10.1016/s1388-1981(02)00217-2 .
• Pawar A, Xu J, Jerks E, Mangelsdorf DJ, Jump DB . Fatty acid regulation of liver X receptors (LXR) and peroxisome proliferator-activated receptor alpha (PPARalpha) in HEK293 cells . The Journal of Biological Chemistry . 277 . 42 . 39243–50 . Oct 2002 . 12161442 . 10.1074/jbc.M206170200 . free .
• Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity . Molecular Endocrinology . 16 . 9 . 2065–76 . Sep 2002 . 12198243 . 10.1210/me.2001-0194 . free .
• Oberkofler H, Schraml E, Krempler F, Patsch W . Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha . The Biochemical Journal . 371 . Pt 1 . 89–96 . Apr 2003 . 12470296 . 1223253 . 10.1042/BJ20021665 .
• Wang M, Thomas J, Burris TP, Schkeryantz J, Michael LF . Molecular determinants of LXRalpha agonism . Journal of Molecular Graphics & Modelling . 22 . 2 . 173–81 . Nov 2003 . 12932788 . 10.1016/S1093-3263(03)00159-1 .
• Fukuchi J, Song C, Ko AL, Liao S . Transcriptional regulation of farnesyl pyrophosphate synthase by liver X receptors . Steroids . 68 . 7–8 . 685–91 . Sep 2003 . 12957674 . 10.1016/S0039-128X(03)00100-4 . 6023862 .

Notes and References

1. Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP . The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling . The Journal of Biological Chemistry . 271 . 16 . 9189–92 . Apr 1996 . 8621574 . 10.1074/jbc.271.16.9189 . free .
2. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ . LXR, a nuclear receptor that defines a distinct retinoid response pathway . Genes & Development . 9 . 9 . 1033–45 . May 1995 . 7744246 . 10.1101/gad.9.9.1033 . free .
3. http://mend.endojournals.org/content/25/4/584.abstract
4. Christoffolete MA, Doleschall M, Egri P, Liposits Z, Zavacki AM, Bianco AC, Gereben B . Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway . The Journal of Endocrinology . 205 . 2 . 179–86 . 2010 . 20176747 . 3133926 . 10.1677/JOE-09-0448 .
5. Korf H, Vander Beken S, Romano M, Steffensen KR, Stijlemans B, Gustafsson JA, Grooten J, Huygen K . Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice . The Journal of Clinical Investigation . 119 . 6 . 1626–37 . Jun 2009 . 19436111 . 2689129 . 10.1172/JCI35288 .
6. Web site: Entrez Gene: nuclear receptor subfamily 1.
7. Gupta DS, Kaul D, Kanwar AJ, Parsad D . Psoriasis: crucial role of LXR-alpha RNomics . Genes and Immunity . 11 . 1 . 37–44 . Jan 2010 . 19798078 . 10.1038/gene.2009.63 . free .
8. Brendel C, Gelman L, Auwerx J . Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism . Molecular Endocrinology . 16 . 6 . 1367–77 . Jun 2002 . 12040021 . 10.1210/mend.16.6.0843 . free .
9. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity . Molecular Endocrinology . 16 . 9 . 2065–76 . Sep 2002 . 12198243 . 10.1210/me.2001-0194 . free .
10. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH . Leptin therapy in insulin-deficient type I diabetes . . 107 . 11 . 4813–9 . 2010 . 10.1073/pnas.0909422107 . 2841945 . 20194735. free . 2010PNAS..107.4813W .
11. Wang Z, Sadovnick AD, Traboulsee AL, Ross JP, Bernales CQ, Encarnacion M, Yee IM, de Lemos M, Greenwood T, Lee JD, Wright G, Ross CJ, Zhang S, Song W, Vilariño-Güell C . Nuclear Receptor NR1H3 in Familial Multiple Sclerosis . Neuron . 90 . 5 . 948–54 . 2016 . 27253448 . 5092154 . 10.1016/j.neuron.2016.04.039 .
12. Antel J, Ban M, Baranzini S, Barcellos L, Barizzone N, Beecham A, Berge T, Bernardinelli L, Booth D, Bos S, Buck D, etal . International Multiple Sclerosis Genetics Consortium . NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk . Neuron . 92 . 2 . 333–335 . October 2016 . 27764667 . 5641967 . 10.1016/j.neuron.2016.09.052 .