SAT-671 Heterozygous Loss of Brca1 in Mice Predisposes to Hepatic Steatosis

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Abstract Disclosure: L. Qiao: None. S. Palikhe: None. P. Dhorajiya: None. P. Bhardwaj: None. C. Kutz: None. J. Thyfault: None. K. McCartney: None. K.A. Brown: None. BRCA1 is a tumor suppressor best characterized for its role in the repair of DNA double-strand breaks. Germline mutations in BRCA1 increase the risk of breast and ovarian cancer. In the general population, obesity is known to increase the risk of 13 types of cancer. Recently, we demonstrated that obesity and poor metabolic health are associated with more DNA damage in the normal breast tissue of BRCA1 mutation carriers and an increased likelihood of developing mammary tumors in Brca1 heterozygous KO (Brca1 het KO) C57Bl/6 mice. Through these studies we discovered that female Brca1 het KO mice on a high fat diet developed liver steatosis, also known as metabolic dysfunction-associated fatty liver disease (MASLD). Since female mice are usually protected from diet-induced MASLD, we hypothesized that heterozygous loss of Brca1 predisposes to MASLD. To examine differences in diet-induced MASLD in Brca1 het KO mice vs wild-type (wt) mice, we performed a study where 4-week old female mice were fed either a low-fat diet (LFD; 10% calories from fat) or a high-fat diet (60% calories from fat) for 22 weeks. Our results showed that HFD-fed Brca1het KO mice tended to gain more body weight than wt mice, and had impaired glucose tolerance, suggesting that heterozygous loss of Brca1 increases susceptibility to obesity and metabolic dysfunction. To test the liver-intrinsic effect of heterozygous loss of Brca1, we performed studies using liver slices from 5-week old female mice, before any signs of overt steatosis, under control conditions or in the presence of palmitate for 24h. We observed more fat accumulation in the liver explants from Brca1 het KO mice compared to those from wt mice, both in control conditions and in the presence of palmitate, suggesting potentially increased de novo lipogenesis, and changes in lipid import, metabolism and/or export. These findings provide novel insights into a role of Brca1 in hepatic lipid metabolism and storage, and suspect that loss of function mutations may predispose to metabolic dysfunction. These changes could also contribute to increase the risk of multiple cancers. Presentation: Saturday, July 12, 2025

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