히드록시카르본산수용체2

Hydroxycarboxylic acid receptor 2
HCAR2
식별자
에일리어스HCAR2, GPR109A, HCA2, HM74a, HM74b, NIACR1, PUMAG, Puma-g, 니아신수용체1, 히드록시카르본산수용체2
외부 IDOMIM : 609163 MGI : 1933383 HomoloGene : 4391 GenCard : HCAR2
맞춤법
종.인간마우스
엔트레즈

338442

80885

앙상블

ENSG00000182782

ENSMUSG000045502

유니프로트

Q8TDS4

Q9EP66

RefSeq(mRNA)

NM_177551

NM_030701

RefSeq(단백질)

NP_808219

NP_109626

장소(UCSC)Chr 12: 122.7 ~122.7 MbChr 5: 124 ~124 Mb
PubMed 검색[3][4]
위키데이터
인간 보기/편집마우스 표시/편집

히드록시카르본산수용체2(HCA2)는 [5]니아신수용체1(NIACR1) 및 GPR109A로도 알려져 있으며, 인체에서 HCAR2 [6][7][8][9]유전자에 의해 암호화되는 단백질이다.HCA는2 다른 히드록시카르본산 수용체1 HCA 및 HCA와3 마찬가지로 G 결합i/o G 단백질 결합 수용체(GPCR)[10][11]이다.HCA의2 주요 내인성 작용제는 D-β-히드록시낙산 및 낙산(및 이들의 결합염기, β-히드록시낙산 및 [10][11]낙산)이다.HCA는2 또한 니아신(일명 니코틴산)[8][9]의 고친화성 생체 분자 표적이다.

HCA2 활성화는 지방 분해 및 무생물 활동을 억제하고(즉, 지방의 분해와 아테롬성 동맥경화증의 발생을 억제), 혈관확장(즉, 혈관의 확장)을 유도하며, 나이아신 유도 [12]홍조를 중재하는 역할을 한다.

기능.

Gi/Go-coupled G니코틴산(니코틴산)[8][9]에 수용체(GPCR)연결 수용체 HCA2은 high-affinity과 GPCRs.HCA2의 활성화, 혈관 확장(즉 dilat을 유발하고 아테롬을 발생시키는 지질 분해성 활동(즉, 지방의 붕괴와, atherosclerosis의 발달을 저해하)부양을 방해하는 니코틴산 수용체 가족의 일원이다.blo의 이온od vessel) 및 니아신 유도 [13]플러싱의 원인이 됩니다.

5-oxo-ETE

HCA의2 마우스 오솔로그인 Niacr1은 5-HEE 계열의 멤버인 5-oxo-ETE가 스테로이드제닉 급성 조절단백질 mRNA, 스테로이드제닉 급성 조절단백질 및 그에 따라 배양된 마우스 MA-10 레이디지세포에서 [14]프로게론의 생성을 촉진하는 능력을 중재하는 것이 제안되었다.인간의 조직은 OXER1 G 단백질 결합 수용체를 통해 5-oxo-ETE 및 기타 5-HETE족에 반응한다.다른 5-HETE 계열에 대한 레이디지 세포 반응에서 Niacr1의 역할, 5-HETE 계열에 대한 다른 마우스 세포 반응에서 Niacr1의 역할, 5-HETE 계열에 대한 인체 조직의 반응에서 HCA의2 역할은 결정되지 않았다.

임상적 의의

HCA는2 이상지질혈증 치료와 HDL 콜레스테롤 증가를 위해 널리 처방되는 약물인 [15]니아신의 중요한 생체 분자 표적이다. 그러나 치료적 사용은 플러싱에 의해 제한된다.HCA2 녹아웃 마우스에서는 지질과[16][17] 플러싱 모두에 대한 나이아신의 영향이 제거된다.또, 아레스틴 베타 1 녹아웃 마우스에서는, 지질 수식 효과를 유지하면서,[18] 니아신의 플러싱 효과를 큰폭으로 저감 한다.높은 용량에서, 니아신은 [19][20][21][22]HCA의2 활성화를 통해 뇌, 위장관, 피부 및 혈관 조직을 포함한 다양한 조직에서 현저한 항염증 효과를 일으킨다.니아신은 또한 NIACR1 [19]결합을 통해 신경 염증을 부분적으로 감소시키는 것으로 나타났다. 따라서 HCA는2 다발성 경화증 및 파킨슨병과 [19][22]같은 신경 면역 장애를 치료하기 위한 잠재적 치료 대상으로 확인되었다.

나이아신 치료 효과의 정확한 작용 메커니즘은 완전히 설명되지 않았지만, 부분적으로 세포 내 cAMP의 수치를 감소시켜 지방세포의 [23]지방 분해를 억제하는2 HCA의 활성화를 통해 작동하는 것으로 보인다.반면 플러싱 효과는 아레스틴 베타 [18]1에 의해 매개되는 ERK 1/2 MAP[24] 키나제의 HCA2 활성화에 기인한다.MAP 키나제의 활성화는 차례로 [25]피부의 랑게르한스 세포에서 프로스타글란딘 D2의 방출을 일으킨다.

NIACR1은 많은 세포 [26][27]유형에서 베타-히드록시낙산염의 항염증 효과에 필수적이지만, 대식세포에서 베타-히드록시낙산염에 의한 NLRP3 염증 억제는 NIACR1과는 무관하다.[28]

리간드

HCA의2 완전한 작용제는 다음을 포함한다.

레퍼런스

  1. ^ a b c GRCh38: 앙상블 릴리즈 89: ENSG00000182782 - 앙상블, 2017년 5월
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  15. ^ Pike NB (December 2005). "Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid". The Journal of Clinical Investigation. 115 (12): 3400–3. doi:10.1172/JCI27160. PMC 1297267. PMID 16322787.
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  22. ^ a b Wakade C, Chong R (December 2014). "A novel treatment target for Parkinson's disease". Journal of the Neurological Sciences. 347 (1–2): 34–8. doi:10.1016/j.jns.2014.10.024. PMID 25455298. S2CID 29760853. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.
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  29. ^ Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (April 2015). "Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation". Nutrients. 7 (4): 2839–49. doi:10.3390/nu7042839. PMC 4425176. PMID 25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.
  30. ^ Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). "The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome". Frontiers in Immunology. 6: 61. doi:10.3389/fimmu.2015.00061. PMC 4332351. PMID 25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192).
    그림 1: 미생물 유래 분자는 대장 트레그 분화를 촉진한다.