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

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 .