Regulation of Betaine Homocysteine Methyltransferase by Liver Receptor Homolog-1 in the Methionine Cycle

Abstract

Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1^f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.

Keywords:

• BHMT
• LRH-1
• liver
• methionine cycle
• triglycerides

Acknowledgments

We thank Prof. Timothy F. Osborne for his kind gift of the Lrh^fl/fl mice. We also thank Prof. Eun Hee Koh for kindly gifting us the albumin-Cre mice.

Authors’ Contributions

Han HK and Mukherjee S contributed to the design and performance of the experiments, analysis and interpretation of data, and writing of the manuscript; Park SY, Lee JH, Lee EH, Kim S, Lee YH, Song DK, Lee S, and Bae JH contributed to the analysis and interpretation of data and critical review of the manuscript; Im SS contributed to the conception and design of the experiments and wrote the manuscript; Im SS is a guarantor of this work, had full access to the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Data Availability Statement

The original contributions presented in the study for the RNAseq analysis are submitted in the SRA database with the accession number PRJNA1081499. CHIP-Seq data are available from our previous paper,⁷ https://doi.org/10.5483/bmbrep.2021.54.9.051. Additional data are available from the corresponding author upon request.

Disclosure Statement

The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Additional information

Funding

This study was supported by grants from the Korea Research Foundation, which were NRF grants funded by the Korean government (NRF-2023R1A2C3003717) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1324).