Article
Multidisciplinary Sciences
Laetitia Coassolo, Tianyun Liu, Yunshin Jung, Nikki P. Taylor, Meng Zhao, Gregory W. Charville, Silas Boye Nissen, Hannele Yki-Jarvinen, Russ B. Altman, Katrin J. Svensson
Summary: Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disease with unclear molecular mechanisms. By analyzing single-cell RNA sequencing data, this study identifies previously unknown clusters of hepatocytes with distinct lipid signatures and uncovers high constitutive androstane receptor (CAR) expression as a novel driver of NAFLD. The study further reveals the functional modules associated with CAR and demonstrates the correlation between CAR expression and steatohepatitis in human livers. These findings provide valuable insights into the cellular differences in lipid signatures and the underlying mechanisms of hepatic steatosis.
Article
Biochemistry & Molecular Biology
Mireia Lopez-Riera, Rebeca Ortega, Luisa Hueso, Maria Carmen Montesinos, Mari Carmen Gomez-Cabrera, Maria Jesus Sanz, Jose T. Real, Laura Piqueras
Summary: This study demonstrates that CAR agonists can inhibit the early inflammatory response that precedes atherosclerosis by targeting various steps in the leukocyte recruitment cascade. This suggests that CAR agonists may serve as a new therapeutic approach to control inflammation associated with cardiovascular diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Congrong Niu, Bill Smith, Yurong Lai
Summary: This study characterized the gene induction by ligands of CAR and AhR in human hepatocytes, showing distinct effects on metabolizing enzyme and drug transporter genes. Different inducers had varying degrees of effects on specific genes, highlighting the importance of assessing transporter gene inductions alongside metabolizing enzyme genes.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Nutrition & Dietetics
Dicson Sheeja Malar, Mani Iyer Prasanth, Kanika Verma, Anchalee Prasansuklab, Tewin Tencomnao
Summary: In this study, the mode of toxicity of Phenanthrene (Phe) in human keratinocytes was investigated, along with the protective effect of the ethanol extract of Hibiscus sabdariffa calyxes (HS). The results showed that Phe induced cytotoxicity through CAR/PXR/RXR-mediated activation of CYP1A1, leading to alterations in phase I and II metabolism genes. However, pre-treatment with HS extract inhibited CYP1A1 and attenuated the pathological changes caused by Phe exposure.
Article
Biochemistry & Molecular Biology
Bhaswati Banerjee, Olayemi Joseph Olajide, Giulia Bortolussi, Andres F. Muro
Summary: Bilirubin is a byproduct of heme metabolism, and Ugt1a1 is the enzyme responsible for its elimination. Dysfunctional Ugt1a1 can lead to the accumulation of unconjugated bilirubin in the brain, causing neuronal damage and death. Understanding alternative bilirubin detoxification mechanisms is crucial for developing new therapeutic strategies. Activation of alternative clearance pathways can partially improve hyperbilirubinemic conditions in the absence of Ugt1a1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Shin-Hun Juang, Min-Tsang Hsieh, Pei-Ling Hsu, Ju-Ling Chen, Hui-Kang Liu, Fong-Pin Liang, Sheng-Chu Kuo, Chen-Yuan Chiu, Shing-Hwa Liu, Chen-Hsi Chou, Tian-Shung Wu, Hsin-Yi Hung
Summary: In the study, 6,7-diprenoxycoumarin was identified as the most effective CAR activator, with modifications at the 6 position and unsaturated chains generally beneficial. The research also indicated that mimicking natural occurring coumarins for modification shed light on CAR studies.
Article
Cell Biology
Fabiana Oliviero, Wendy Klement, Lucile Mary, Yannick Dauwe, Yannick Lippi, Claire Naylies, Veronique Gayrard, Nicola Marchi, Laila Mselli-Lakhal
Summary: Non-Alcoholic Fatty Liver Disease (NAFLD) is a common chronic liver disease, especially in obese individuals. This study suggests that the nuclear receptor CAR may play a role in the pathogenesis of NAFLD and could be a potential therapeutic target. In mice, deletion of CAR led to a NASH-like hepatic transcriptomic signature and astrogliosis in the hypothalamus of female mice.
Article
Endocrinology & Metabolism
Ye Feng, Dan Xu, Xinran Cai, Meishu Xu, Wojciech G. Garbacz, Songrong Ren, Michael J. Jurczak, Chaohui Yu, Hui Wang, Wen Xie
Summary: The study found that GDM is a key risk factor for future development of metabolic disease, and CAR could be a therapeutic target for managing metabolic diseases sensitized by GDM.
Article
Multidisciplinary Sciences
Melissa M. Heintz, Jazmine A. Eccles, Emily M. Olack, Kristal M. Maner-Smith, Eric A. Ortlund, William S. Baldwin
Summary: In addition to over consumption, multiple factors contribute to obesity and non-alcoholic fatty liver disease (NAFLD). CYP2B6, a human detoxification enzyme, has been found to be associated with obesity. It metabolizes PUFAs, with a preference for ALA metabolism and PUFAs at the 9- and 13-positions. Research using transgenic mice showed that CYP2B6 has an anti-obesity effect, but to a lesser extent compared to Cyp2b in mice. The inhibition of CYP2B6 by xenobiotics or dietary fats can worsen obesity and metabolic disease by disrupting PUFA metabolism and producing key lipid metabolites.
Article
Nutrition & Dietetics
Xuan Xiang, Houfu Wang, Wentao Zhou, Chenyu Wang, Peng Guan, Gang Xu, Qiang Zhao, Liuqin He, Yulong Yin, Tiejun Li
Summary: This study investigated the regulatory mechanism of different dietary levels of endogenous glutathione (GSH) supplementation on the intestinal barrier and antioxidant function in a paraquat-induced stress-weaned piglet model. The results showed that dietary 0.06% GSH supplementation improved the growth performance and reduced diarrhea rate of weaned piglets. GSH also protected against oxidative stress damage by regulating intestinal morphology, organelle, and permeability, as well as modulating antioxidant and anti-inflammatory gene expression.
Review
Biochemistry & Molecular Biology
Sarah Da Won Bae, Romario Nguyen, Liang Qiao, Jacob George
Summary: CAR is a receptor that is predominantly expressed in the liver and interacts with key signaling pathways related to drug, energy, and bilirubin metabolism. While studies in animal models suggest a potential role of CAR in tumorigenesis, recent research has shown species differences and a possible tumor-suppressive role of CAR in liver cancer in humans. This review highlights the need for further exploration of CAR's role in human diseases, particularly cancers, with a focus on its emerging functions in liver cancer.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Environmental Sciences
Yu-Sheng Shi, Yi Zhao, Xue-Nan Li, Mu-Zi Li, Jin-Long Li
Summary: Phthalates, extensively used in plastics production, have been proven to cause lung injury. Lycopene (LYC) is an effective preventive measure against phthalates-induced toxicity. However, the role of phthalates in the pathogenesis of lung injury and whether LYC can alleviate phthalate-induced lung toxicity by modulating nuclear xenobiotic receptors (NXRs) response have not been thoroughly researched. This study investigates the toxicity of the representative phthalate di (2-ethylhexyl) phthalate (DEHP) and the antagonistic role of LYC in DEHP-induced lung injury. It was found that DEHP exposure caused alveoli destruction and damage to alveolar epithelial cells type II. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes, as well as Constitutive androstane receptor (CAR) and its downstream gene level. LYC supplementation relieved lung injury from DEHP exposure by inhibiting the activation of NXRs. The study confirms the important role of NXRs in phthalates-induced lung injury and suggests LYC as an effective strategy for mitigating the toxicity effects of phthalates.
Article
Pharmacology & Pharmacy
Yoshihiro Kobashigawa, Mana Namikawa, Mitsuhiro Sekiguchi, Yuki Inada, Soichiro Yamauchi, Yuu Kimoto, Kyo Okazaki, Yuya Toyota, Takashi Sato, Hiroshi Morioka
Summary: The constitutive active/androstane receptor (CAR) is a nuclear receptor involved in drug metabolism regulation. A novel system was developed for rapid evaluation of drug interactions with CAR, using differential scanning fluorometry (DSF) to confirm direct interactions. This method is easy to set up and beneficial for drug discovery purposes.
BIOLOGICAL & PHARMACEUTICAL BULLETIN
(2021)
Article
Biochemistry & Molecular Biology
Hangxing Huang, Change Cao, Zhimin Miao, Xiaoli Yang, Yong Lai
Summary: In this study, it was found that scutellarin can affect the expression of CYP3A4 and CYP2C19 in HepG2 and Caco-2 cells by regulating nuclear receptors PXR and CAR. Scutellarin inhibits the expression of CYP3A4 through PXR, and up-regulates CYP2C19 through CAR.
CURRENT MOLECULAR PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Shijia Pan, Yuan Guo, Wen Yu, Jia Zhang, Xiaoxiao Qiao, Letong Li, Pengfei Xu, Yonggong Zhai
Summary: Environmental chemicals, such as the CAR-specific ligand TC, have detrimental effects on offspring health, including inhibition of body weight, altered hepatic drug metabolism, distorted intestinal morphology, impaired barrier integrity, and disrupted lipid uptake and transport. Mechanistically, maternal TC exposure triggers an inflammatory response and impairs the antioxidant system in offspring, hindering nutrient absorption and posing a serious threat to offspring health.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)