Alcohol consumption exacerbates high-fat diet-mediated disruptions in myelopoiesis and osteoclastogenesis in mouse models of metabolic dysfunction-associated liver diseases.

Abstract

OBJECTIVE: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Alcohol-related Liver Disease (MetALD) exhibit systemic immune abnormalities. Given that such immune dysregulation is closely linked to the skeletal complications frequently observed in MASLD and MetALD, we sought to comprehensively characterize the bone marrow hematopoietic compartment and its link to osteoclastogenesis. METHODS: We utilized bone marrow from mouse models of MASLD (high-fat diet, HFD) and MetALD (high-fat diet plus ethanol, HFD+EtOH), followed by flow cytometric analysis to phenotype hematopoietic stem and progenitor cells (HSPCs), as well asandassays to evaluate osteoclastogenesis. RESULTS: We found that HFD depletes the hematopoietic stem cell (HSC) and early multipotent progenitors, whereas HFD+EtOH preserves HSC and skews hematopoiesis toward myeloid-committed multipotent progenitors, resulting in the expansion of Ly6Chigh progenitors and monocytes. Further, enrichment of committed osteoclast precursors (CD115RANK) was significantly greater in the HFD+EtOH compared to HFD alone. This was associated with increased RANK expression in Ly6Chigh precursors and was accompanied by enhanced osteoclast multinucleation, cell area, and elevated resorptive activity in osteoclasts derived from the HFD+EtOH group. Bone analysis revealed elevated osteoclast activity, along with increased epiphyseal area and femur length, in HFD+EtOH-fed mice, potentially due to delayed chondrocyte hypertrophy/prolonged growth plate activity. CONCLUSION: Collectively, these findings demonstrate that while both HFD and HFD+EtOH trigger diet-specific hematopoietic alterations, alcohol amplifies the HFD-induced effects, promoting the expansion of myeloid and osteoclast precursors, thereby enhancing osteoclastogenesis. These findings highlight the need to consider hematopoietic health in patients with MASLD and MetALD and lay the groundwork for future research focused on alleviating immune and skeletal complications associated with metabolic dysfunction-related liver diseases.