Adra1a, also known as the alpha-1A adrenergic receptor, is a crucial component in noradrenaline-mediated signaling. It coordinates with β3-adrenergic receptor (β3-AR) to induce the expression of thermogenic genes in the futile creatine cycle, regulating adipocyte thermogenesis through the ADRA1A-Gαq-futile creatine cycle axis [1]. Additionally, it is involved in multiple physiological and pathological processes, such as lipid metabolism, vascular reactions, and cancer-related events [2,3,5].

In a pregnancy-associated hypertensive (PAH) mouse model, Adra1a-deficient PAH mice exhibited more severe cardiac hypertrophy compared to PAH mice, suggesting that changes in Adra1a expression are involved in progressive cardiac hypertrophy in PAH mice as Adra1a levels are regulated by the renin-angiotensin system [4]. In hepatocellular carcinoma (HCC), the expression of Adra1a is decreased, and its promoter region is hypermethylated. DNA methyltransferase inhibitor can increase its expression, and its hypermethylation is associated with clinical characteristics of HCC, making it a potential biomarker for HCC diagnosis [2]. Also, in non-alcoholic fatty liver disease (NAFLD), leonurine may improve hepatic lipid metabolism through the Adra1a/AMPK/SCD1 axis [3].

In conclusion, Adra1a is essential in regulating adipocyte thermogenesis, lipid metabolism, and vascular reactions. Gene-knockout mouse models, like those in PAH research, have revealed its role in cardiac hypertrophy. Its association with diseases such as HCC and NAFLD indicates its potential as a biomarker and a target for therapeutic intervention, highlighting the importance of further functional studies on Adra1a in understanding disease mechanisms and developing treatments.

References:

1. Rahbani, Janane F, Scholtes, Charlotte, Lagarde, Damien M, Giguère, Vincent, Kazak, Lawrence. 2022. ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP. In Nature metabolism, 4, 1459-1473. doi:10.1038/s42255-022-00667-w. https://pubmed.ncbi.nlm.nih.gov/36344764/

2. Chen, Guoqiao, Fan, Xiaoxiao, Li, Yirun, Zhou, Daizhan, Lin, Hui. 2020. Promoter aberrant methylation status of ADRA1A is associated with hepatocellular carcinoma. In Epigenetics, 15, 684-701. doi:10.1080/15592294.2019.1709267. https://pubmed.ncbi.nlm.nih.gov/31933413/

3. Fan, Wen, Pan, Maoxing, Zheng, Chuiyang, Yang, Qinhe, Zhang, Yupei. 2024. Leonurine Inhibits Hepatic Lipid Synthesis to Ameliorate NAFLD via the ADRA1a/AMPK/SCD1 Axis. In International journal of molecular sciences, 25, . doi:10.3390/ijms251910855. https://pubmed.ncbi.nlm.nih.gov/39409181/

4. Kim, Jun-Dal, Kwon, Chulwon, Nakamura, Kanako, Nakagawa, Yoshimi, Fukamizu, Akiyoshi. 2023. Increased angiotensin II coupled with decreased Adra1a expression enhances cardiac hypertrophy in pregnancy-associated hypertensive mice. In The Journal of biological chemistry, 299, 102964. doi:10.1016/j.jbc.2023.102964. https://pubmed.ncbi.nlm.nih.gov/36736425/

5. Baranova, Tatyana, Podyacheva, Ekaterina, Zemlyanukhina, Tatyana, Glotov, Oleg, Glotov, Andrey. 2022. Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes. In International journal of molecular sciences, 23, . doi:10.3390/ijms23169433. https://pubmed.ncbi.nlm.nih.gov/36012699/