MON-708 - Brca1 Heterozygous Loss Leads to Metabolic Dysfunction-Associated Steatotic Liver Disease in Male and Female Mice Despite Sexually Dimorphic Effects on Whole Body Energy Balance

BRCA1 is a tumor suppressor best known for its role in DNA double-strand break repair, and germline BRCA1 mutations markedly increase the risk of breast and ovarian cancers. Obesity and poor metabolic health are established risk factors for multiple cancer types and have recently been shown to be associated with high risk of breast cancer in BRCA1 mutation carriers. However, the metabolic consequences of BRCA1 haploinsufficiency remain poorly understood. To evaluate the metabolic effects of Brca1 heterozygous loss, four-week-old female and male heterozygous Brca1 knockout (Brca1+/–) and wild-type (WT) C57BL/6 mice were fed either a low-fat diet (LFD; 10% kcal from fat) or high-fat diet (HFD; 60% kcal from fat) for 22 weeks. HFD-fed Brca1+/– female mice were found to have higher body weight compared WT HFD-fed female mice (WT: 35.9 g ± SD: 7.2 vs Brca1+/-: 42.8 g ± SD: 4.8, p = 0.02). Conversely, WT male mice had higher body weight compared to Brca1+/– male mice (WT: 48.3 ± SD: 2.8 vs Brca1+/-: 44.5 ± SD: 3.0, p = 0.05). Brca1+/– HFD-fed female mice were found to be more glucose intolerant by glucose-tolerance test (GTT) compared to WT HFD-fed female mice (AUC WT: 6,355 ± SD: 1,333 vs Brca1+/-: 9,009 ± SD: 2,869, p = 0.02). However, in males, WT HFD-fed mice that showed higher glucose intolerance (AUC WT: 12,054 ± SD: 2,735 vs Brca1+/-: 10,380 ± SD: 2,822, p = 0.04). Brca1+/– HFD-fed female mice were shown to have higher lean mass compared to WT HFD-fed female mice, while WT HFD-fed male mice had higher fat mass compared to Brca1+/– HFD-fed male mice. In Brca1+/– HFD-fed female mice, adipocyte diameter in gonadal white adipose tissue (gWAT) was larger in WT HFD-fed female mice (WT: 106.1 microns ± SD: 14.1 vs Brca1+/-: 120.9 ± SD: 9.7, p = 0.03), which was not observed in male mice (WT: 103.0 microns ± SD: 17.8 vs Brca1+/-: 108.1 microns ± SD: 13.7, p = 0.48). Notably, fat accumulation in the livers of both male and female mice was noticeably elevated compared to WT mice, indicating liver steatosis, also known as metabolic dysfunction-associated fatty liver disease (MASLD). Lipid droplet analysis was performed in females, with lipid droplet area per hepatocyte being higher in HFD-fed Brca1+/- mice compared to WT controls (WT: 39.2 micron2 ± SD: 19.1 vs Brca1+/-: 73.6 micron2 ± SD: 27.8, p = 0.04).
These findings demonstrate that heterozygous loss of Brca1 leads to pronounced metabolic alterations with distinct sex-specific effects. Predisposition to MASLD in both males and females suggest liver-intrinsic effects. These metabolic disturbances may represent early events that predispose to cancer development, underscoring the importance of metabolic health in the context of BRCA1 deficiency.

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