MASLD - Obesity-driven aquired sex diversity and its implications for the progression of Metabolic Dysfuntion-associated Steatotic Liver diesease

Metabolie dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, driven by the rising prevalence of obesity and the metabolic syndrome. Despite its clinical significance, the underlying molecular mechanisms that determine disease progression, particularly in relation to adipose tissue function in obesity, associated sex differences and steroid hormone signaling, remain incompletely understood. Notably, progression to steatohepatitis (MASH), fibrosis and hepatocellular carcinoma (HCC) exhibits a striking male predominance, further pointing to sex-specific modulators of disease risk. 

Recent findings from our consortium indicate that steroid profiles in individuals with obesity do not follow a binary sex pattern, but rather span a continuum, suggesting a state of "acquired sex diversity". Transcriptomic analyses of subcutaneous, visceral adipose and hepatic tissues have revealed depot- and stage-specific gene expression patterns, implicating adipose tissue as hormonally active organ that may directly influence liver inflammation. This project aims to characterize sex steroid profiles in a well-phenotyped MASLD cohort across the full range of disease stages with a focus on obesity and related sex differences. Steroid hormone levels will be measured in serum samples from non-obese and obese men and women with MASH, individuals with MASH-related HCC, and 12 months after bariatric surgery to assess MASH resolution. The differences in serum steroids obtained will be functionally evaluated using precision-cut liver slices (PCLS) from patients living with MASLD, followed by further molecular analysis. 

Ultimately, the project aims to identify sex-specific and obesity-modulated hormonal signals that contribute to MASH progression, potentially enabling novel personalized therapeutic strategies.