Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Female mice exhibit reduced hallmarks of metabolic dysfunction-associated steatohepatitis (MASH) than males in the GAN-DIO preclinical model of MASH. (#188)

Isabella A. Simon 1 , Khashayar Asadi 2 , Yu-Anne Yap 3 , Remy Robert 3 , Avik Majumdar 2 , Robert Jones 2 , Robert E. Widdop 1 , Mark Del Borgo 1
  1. Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Liver Transplant Unit, Austin Hospital, Heidelberg, VIC, Australia
  3. Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia

Introduction. Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of the newly coined metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as NAFLD) and one of the leading causes for liver disease worldwide. MASH is also the leading indication of liver transplantation in women and the 2nd leading cause in men, following ALD (1). A diet-induced obesogenic (DIO) model known as the Gubra-amylin NASH (GAN)-DIO model is considered to be the gold standard preclinical model of MASH (2). To date, there have been no studies investigating sex differences in the development and progression of MASH using this model.

Methods. Male and female C57Bl6 mice (5-6 weeks of age) were fed GAN-DIO feed consisting of saturated fat (46%), fructose (22%), sucrose (10%) and cholesterol (2%) for up to 36 weeks. Excised liver tissue was processed for H&E and picrosirius red staining to score tissues using the NAS-CRN score (scoring steatosis, inflammation and hepatocellular ballooning) and fibrosis staging.

Results. MASH, defined as NAS-Score ≥5 out of 8, was confirmed in male mice from 22weeks of feeding. At 36 weeks, all male mice received a NAS-Score ≥5, with majority scoring either a 6 or 7 (33.3% each) and a small proportion scoring an 8 (6.7%). Overall, female mice had lower NAS scores, with a proportion (12.5%) scoring less than 5. Picrosirius red staining showed a higher proportion of males than females exhibited advanced fibrosis at 36weeks (stage F4; 33.3% and 12.5% respectively). Similarly, females also had a greater proportion of mild fibrosis (stage F1) compared to males at 36 weeks (50.0% and 13.3% respectively).

Discussion & Conclusion. Females exhibited lower NAS-scores and fibrosis staging than males, suggesting they were protected from MASH. The role of the protective arm of the renin angiotensin system is being investigated in this context.

  1. Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, et al. NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol. 2018 Nov;113(11):1649–59.
  2. Hansen HH, Ægidius HM, Oró D, Evers SS, Heebøll S, Eriksen PL, et al. Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis. BMC Gastroenterol. 2020 Jul 6;20(1):210.