ORF29-08 - Androgen Excess Protects Against MASLD Independently of Hepatic Androgen Receptor and Insulin Resistance in Females

Androgen excess (AE), a common feature of polycystic ovary syndrome, congenital adrenal hyperplasia, and gender-affirming hormone therapy, is a known driver of insulin resistance (IR), yet how AE influences hepatic lipid homeostasis is not well understood. In age and weight matched female mice, dihydrotestosterone (DHT) treatment under a regular chow diet did not alter hepatic or circulating lipid levels. However, under a western diet (WD), DHT protected against metabolic dysfunction associated steatotic liver disease (MASLD) by reducing hepatic triglyceride (TG) accumulation, while simultaneously exacerbating systemic hypertriglyceridemia and IR, without altering hepatic insulin–Akt signaling. This protection against MASLD occurred independently of hepatic androgen receptor (AR) signaling. Multi-omics profiling revealed that DHT remodeled hepatic transcription toward a male-like lipid regulation driven by pulsatile growth hormone (GH)–STAT5 signaling. DHT enhanced hepatic STAT5 activation, suppressed expression of the fatty acid (FA) transporter Cd36, and reduced hepatic FA uptake, while increasing very low density lipoprotein triglyceride (VLDL-TG) secretion. Continuous GH infusion, which mimics the female GH secretion pattern, reversed these effects by attenuating STAT5 activation and restoring Cd36 expression. Moreover, steatosis that had already developed in WD fed mice was improved by subsequent DHT treatment. Together, these findings identify a GH dependent, hepatic AR and insulin independent pathway through which AE regulates hepatic lipid homeostasis.