Sabine Daemen1, Tuneille Adelaar1, Margee Teunissen1, Casper Schalkwijk1, Kristiaan Wouters1
1Dept. of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
scm.daemen@maastrichtuniversity.nl
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver disease and is closely linked to obesity and type 2 diabetes. In fact, an estimate of 65% of people with type 2 diabetes have MASLD. MASLD is characterized by liver steatosis, and 20–30% of individuals progress to metabolic dysfunction-associated steatohepatitis (MASH), marked by immune cell infiltration and activation. MASH can progress to liver fibrosis, strongly increasing the risk of intra- and extrahepatic complications. MASH and related complications show clear sex differences, yet the underlying immunometabolic drivers remain poorly understood. This study aimed to characterize hepatic and systemic immunometabolic alterations during MASH progression in both sexes.
Methods: Male and female mice received the Gubra-Amylin NASH diet (40% kcal fat (including 15% palm oil), 2% cholesterol, 20% fructose) or matched control diet for 10, 15, 20 or 25 weeks. MASH development and systemic metabolic and inflammatory changes were assessed using histology, spectral flow cytometry, biochemical lipid assays and glucose tolerance tests.
Results: Both sexes exhibited limited weight gain and no significant increase in adiposity. Infiltration of monocyte-derived macrophages (MdMs), a key hallmark of MASH inflammation, occurred earlier in females (onset at 15 weeks, control 7913±2749 vs. MASH 75462±54670 MdM count/gr liver, p=0.004) than males (15 weeks control 5637±1622 vs. MASH 43170±57507 MdM count/gr liver, p=0.139). Female mice demonstrated overall higher liver steatosis (steatosis score MASH females 1.68±0.65 vs. males 1.05±0.49, p=0.001), whereas fibrosis occurred almost exclusively in males (fibrosis score MASH females 0.32±0.48 vs. males 1.00±0.98, p=0.011). Female mice had earlier onset of glucose intolerance (10 weeks AUC control 1506±257 vs. MASH 2001±261, p=0.003) than males (10 weeks AUC control 1720±342 vs. MASH 1893±343, p=0.401). Inflammation was not observed in visceral or subcutaneous adipose tissue and blood immune cells remained largely unchanged.
Discussion/Conclusion: Sex differences were evident in liver steatosis, inflammation and fibrosis, and glucose intolerance, independent of peripheral inflammatory changes.