{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:09:48Z","timestamp":1785424188165,"version":"3.56.0"},"reference-count":65,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006379","name":"Office of Research and Development","doi-asserted-by":"publisher","award":["I01BX006064"],"award-info":[{"award-number":["I01BX006064"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]},{"award":["I01BX006064"],"award-info":[{"award-number":["I01BX006064"]}],"id":[{"id":"https:\/\/ror.org\/011qyt180","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute of Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["AA030407-1531"],"award-info":[{"award-number":["AA030407-1531"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]},{"award":["AA030407-1531"],"award-info":[{"award-number":["AA030407-1531"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Buffett Cancer Center","award":["P30CA03672"],"award-info":[{"award-number":["P30CA03672"]}]},{"award":["P30CA03672"],"award-info":[{"award-number":["P30CA03672"]}],"id":[{"id":"https:\/\/ror.org\/03n63wv08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Betaine-homocysteine methyltransferase (BHMT) is an enzyme involved in one-carbon metabolism and plays a crucial role in maintaining liver health. In this study, we investigated the impact of liver-specific deletion of BHMT on liver dysfunction using a mouse model. We generated BHMT floxed mice and bred them with albumin Cre to generate liver-specific BHMT knockout (BHMT LKO) mice. Liver tissues harvested from six-month-old chow-fed BHMT floxed and LKO mice were characterized through histological, biochemical, and molecular analyses. BHMT LKO mice displayed a complete loss of hepatic expression of BHMT mRNA, protein and enzyme activity. Histopathological analysis revealed the development of hepatic steatosis in BHMT LKO mice compared to the floxed mice. These morphological changes were supported by biochemical analysis showing elevated levels of hepatic triglycerides in conjunction with a profound decrease in the methylation potential (i.e., reduced S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio), which was mainly driven by a six- to sevenfold increase in SAH levels. BHMT LKO mice also exhibited increased lipid peroxidation and lysosomal dysfunction compared to floxed mice. Early signs of inflammation were seen in the livers of BHMT LKO mice of both sexes, as evident from significant increase in CD68-positive cells and interleukin 1\u03b2 levels. Additionally, there was a moderate increase in fibrosis, as evidenced by the upregulated expression of \u03b1-smooth muscle actin and collagen II levels and the histological assessment of picrosirius red-stained liver sections of BHMT LKO mice of both sexes compared to their respective counterparts. These findings demonstrate that hepatic BHMT deficiency promotes lipid accumulation, lysosomal\/proteasomal dysfunction, and early inflammatory and fibrotic changes in the liver by reducing the methylation potential. Collectively, our results underscore BHMT as a critical regulator of liver homeostasis and a potential therapeutic target in liver-related disorders.<\/jats:p>","DOI":"10.3390\/biom16040606","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte-Specific Deletion of Betaine-Homocysteine Methyltransferase Disrupts Methionine Metabolism and Promotes the Spontaneous Development of Hepatic Steatosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3817-7704","authenticated-orcid":false,"given":"Ramachandran","family":"Rajamanickam","sequence":"first","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0151-521X","authenticated-orcid":false,"given":"Sathish Kumar","family":"Perumal","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5356-350X","authenticated-orcid":false,"given":"Ramesh","family":"Bellamkonda","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-7868","authenticated-orcid":false,"given":"Sundararajan","family":"Mahalingam","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-390X","authenticated-orcid":false,"given":"Kurt W.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolen","family":"Quadros","sequence":"additional","affiliation":[{"name":"Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8022-4033","authenticated-orcid":false,"given":"Channabasavaiah B.","family":"Gurumurthy","sequence":"additional","affiliation":[{"name":"Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0567-7857","authenticated-orcid":false,"given":"Madan Kumar","family":"Arumugam","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Cancer Biology Lab., Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai 600119, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-3957","authenticated-orcid":false,"given":"Karuna","family":"Rasineni","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7759-8889","authenticated-orcid":false,"given":"Kusum K.","family":"Kharbanda","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41392-024-02072-z","article-title":"Liver diseases: Epidemiology, causes, trends and predictions","volume":"10","author":"Gan","year":"2025","journal-title":"Signal Transduct. 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