J Biochem Mol Toxicol. 2026 Nov;40(11):e71141. doi: 10.1002/jbt.71141.
ABSTRACT
β-Hydroxybutyrate dehydrogenase 1 (BDH1) has been implicated in metabolic disorders. Nevertheless, its function and underlying mechanisms in atherosclerosis (AS) remain ambiguous. A high-fat diet-fed apolipoprotein E-deficient mouse model and oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 macrophages were established. BDH1 expression was evaluated by immunofluorescence and Western blot. RAW264.7 cells with BDH1 overexpression or knockdown were treated with MB-3 (acetylation inhibitor) and Ac-CoA Synthase Inhibitor 1 (ACSS2i, β-hydroxybutyrylation pathway inhibitor). Cell viability, lipid deposition, lipid-related indices, inflammatory cytokines, and histone modifications were evaluated. Bioinformatics analysis was performed to screen downstream pathway of BDH1, and the peroxisome proliferator-activated receptor (PPAR) pathway inhibitor GW9662 was applied for functional validation. Herein, BDH1 was markedly downregulated in aortic lesions and plaque macrophages from atherosclerotic mice. In ox-LDL-challenged RAW264.7 cells, BDH1 overexpression increased cell viability and reduced lipid accumulation, triglycerides, total cholesterol, tumor necrosis factor-α, and histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb) levels, while increasing interleukin-10, and histone H3 lysine 9 acetylation (H3K9ac). Conversely, BDH1 knockdown exacerbated these pathological alterations. MB-3 attenuated the protective effects of BDH1 overexpression and its induction of H3K9ac. ACSS2i partially rescued the deleterious effects of BDH1 knockdown, accompanied by reduced H3K9bhb and restored H3K9ac. PPAR pathway was identified as a downstream pathway of BDH1, and PPAR inhibition reversed the benefits of BDH1 overexpression. Collectively, BDH1 protects against ox-LDL-induced macrophage foam cell formation and inflammatory responses, at least in part by modulating histone acylation including H3K9ac and H3K9bhb, and by activating the PPAR signaling pathway.
PMID:42927614 | DOI:10.1002/jbt.71141