Last update 01 Nov 2024

HCAR3

Last update 01 Nov 2024

Basic Info

Synonyms

G protein-coupled receptor 109B, G-protein coupled receptor 109B, G-protein coupled receptor HM74

+ [10]

Introduction

Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet.

Drugs associated with HCAR3

Niacin

Target

HCAR3 x NIACR1

Mechanism

HCAR3 agonists [+1]

Active Org.

KOS Pharmaceuticals, Inc. [+2]

Originator Org.

Astellas Pharma, Inc.

Active Indication

Hypertriglyceridemia [+4]

Inactive Indication

Atherosclerosis [+3]

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date01 Nov 1956

Inositol Nicotinate

Target

HCAR3 x NIACR1

Mechanism

HCAR3 agonists [+1]

Active Org.-

Originator Org.-

Active Indication

Hyperlipidemias [+1]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Simvastatin/Nicotinic Acid

Target

HCAR3 x HMG-CoA reductase x NIACR1

Mechanism

HCAR3 agonists [+2]

Active Org.-

Originator Org.

AbbVie, Inc.

Active Indication

Primary Hyperlipidemia

Inactive Indication-

Drug Highest PhasePhase 3

First Approval Ctry. / Loc.

First Approval Date15 Feb 2008

206

Clinical Trials associated with HCAR3

NCT06582706 / Not yet recruitingPhase 1/2IIT

Nicotinic Acid for the Treatment of Alzheimer's Disease

Increased dietary intake of niacin is correlated with reduced risk of Alzheimer's Disease and age-associated cognitive decline. The goal of this study is to collect data on the penetration of commercially available, FDA approved, extended-release niacin into the spinal fluid. One dose of 500 mg nicotinic acid will be used (in addition to placebo) to build a dose response curve for this compound in human cerebrospinal fluid. This objective will demonstrate target engagement of HCAR2 in the central nervous system, after oral treatment with niacin. The primary endpoints are to show increased nicotinic acid levels in blood and cerebrospinal fluid. A secondary endpoint is to collect safety and tolerability data of niacin in this particular population.

Start Date01 Oct 2024

Sponsor / Collaborator

Indiana University

[+1]

NCT06406140 / Enrolling by invitationPhase 2/3IIT

Potential Effect of Niacin on Lipoprotein (a) Concentration and Hyperphosphatemia in End-Stage Renal Disease Patients Undergoing Hemodialysis

The goal of this clinical trial is to learn if Niacin has an effect on lipoprotein (a) concentration and hyperphosphatemia, which represent strong risk factors for cardiovascular diseases, in End-stage renal disease (ESRD) patients undergoing hemodialysis. It will also learn about the safety of Niacin. The main questions it aims to answer are:
* Does Niacin lower lipoprotein (a) concentration?
* Does Niacin treat hyperphosphatemia in End-stage renal disease (ESRD) patients undergoing hemodialysis? Researchers will compare Niacin to a control group (taking no drug) to see if drug Niacin works to treat hyperphosphatemia and lower lipoprotein (a) concentration.
Participants will:
* Take drug Niacin or no drug every day for 3 months
* Visit the clinic once every 2 weeks for checkups and tests
All Patients will be subjected to the following:
1. Informed consent.
2. Demographics and history taking: Using Patient Data sheet.
3. Laboratory evaluation including:
Kidney function tests: blood urea,serum creatinine, albumin ,uric acid. Complete blood count (CBC). Lipid profile:Lipoprotein (a),total cholesterol,triglyceride,high density lipoprotein (HDL), low density lipoprotein (LDL).
Phosphorous, calcium, sodium, parathyroid hormone (PTH), alkaline phosphatase (ALP).
C-reactive protein (CRP).

Start Date15 Mar 2024

Sponsor / Collaborator

Al-Azhar University

JPRN-jRCT1041230130 / RecruitingEarly Phase 1IIT

Study of metabolite changes by niacin-related supplements on healthy subjects - Niacin metabolism

Start Date11 Jan 2024

Sponsor / Collaborator-

100 Clinical Results associated with HCAR3

100 Translational Medicine associated with HCAR3

0 Patents (Medical) associated with HCAR3

Literatures (Medical) associated with HCAR3

01 Nov 2024·Cell Reports

Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3

Article

Author: Qian, Chungen ; Pan, Xin ; Zhu, Lizhe ; Li, Xinyu ; Zhang, Binghao ; Chen, Geng ; Liu, Aijun ; Ning, Peiruo ; Zhang, Zhiyi ; Wang, Qinggong ; Gong, Kaizheng ; Xiang, Xufu ; Du, Yang ; Li, Jiancheng ; Ye, Fang

Hydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is deeply involved in many physiological processes and serves as a valuable target for the treatment of metabolic diseases, tumors, and immune diseases. Here, we report four cryoelectron microscopy (cryo-EM) structures of human HCAR3-Gi1 complexes with or without agonists: the endogenous ligand 3-hydroxyoctanoic acid, the drug niacin, the highly subtype-specific agonist compound 5c (4-(n-propyl)amino-3-nitrobenzoic acid), and the apo form. Together with mutagenesis and functional analyses, we revealed the recognition mechanisms of HCAR3 for different agonists. In addition, the key residues that determine the ligand selectivity between HCAR2 and HCAR3 were also illuminated. Overall, these findings provide a structural basis for the ligand recognition, activation, and selectivity and G-protein coupling mechanisms of HCAR3, which contribute to the design of HCAR3-targeting drugs with high efficacy and selectivity.

01 Oct 2024·Anticancer Research

Identification of New Potential Targets for Pancreatic Ductal Adenocarcinoma by Integrated Bioinformatic Analysis

Article

Author: Ren, K E ; Li, Rujia ; Zeng, Yuhao ; LI, JUN ; LI, RUJIA ; ZENG, YUHAO ; Yang, Ting ; Li, Jun ; REN, KE ; NAGAKAWA, YUICHI ; Yi, Shuang-Qin ; YI, SHUANG-QIN ; NATSUYAMA, YUTARO ; YANG, TING ; Nagakawa, Yuichi ; Natsuyama, Yutaro

BACKGROUND/AIMPancreatic cancer is the fourth leading cause of cancer-related death in both men and women worldwide. The 5-year relative survival rate for pancreatic ductal adenocarcinoma (PDAC) is 10%, which is the lowest among all cancers. This study aimed to find more effective targets to improve the diagnosis, prognostic prediction, and treatment of PDAC.MATERIALS AND METHODSThree datasets were selected from the GEO database. Correlation analysis was used to screen the datasets and samples. Differentially expressed genes were identified using GEO2R. Metascape was used to perform pathway and process enrichment analysis. Survival analysis using the GEPIA2 and Kaplan-Meier plotter databases was conducted to filter hub genes. Principal component analysis and LASSO regression analyses were used to further filter the key genes. Gene expression in PDAC and normal tissues and in different pathological stages was analyzed using the GEPIA2 database. Thereafter, gene expression was detected in three PDAC and HPDE cell lines using real-time polymerase chain reaction.RESULTSLPAR5, CYP2C18, SERPINH1, ACSL5, and HCAR3 exhibited higher transcription levels in PDAC tissues compared to matched normal tissues, whereas the PNLIP expression was lower. LPAR5, CYP2C18, SERPINH1 and ACSL5 were markedly upregulated in stage IV PDAC. LPAR5, CYP2C18, SERPINH1 and ACSL5 were upregulated in PDAC cell lines. Further verification suggested that the expression levels of these four genes were closely related to histological type, pathologic stage, therapeutic effects and prognosis of pancreatic cancer.CONCLUSIONLPAR5, CYP2C18, SERPINH1 and ACSL5 may serve as potential diagnostic, prognostic, and therapeutic targets for PDAC.

01 Jun 2024·Journal of Investigative Dermatology

GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration

Article

Author: Lund, Katherine ; Chen, Ting ; Pedro, M Pilar ; Porat-Shliom, Natalie ; Kang, Sun Woo Sophie ; Stuelten, Christina H ; Iglesias-Bartolome, Ramiro

Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and GPCRs play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified 3 key receptors-HCAR3, LTB4R, and GPR137-and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.

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