Endocrine Abstracts

Pharmacological inhibition of 5α-reductases (SRD5A1) activity is associated with insulin resistance, dyslipidaemia, and hepatic steatosis in humans, while increased susceptibility to steatosis and liver fibrosis have been observed in mice with disruption of Srd5a1. We aim to identify the potential SRD5A1 regulatory networks underpinning metabolic dysfunction-associated steatotic liver disease (MASLD). We used genomic and hepatic transcriptomic data from Genotype-Tissue Expression Project (GTEx; n = 208, 55.0±13.0 years, 66.9% men) and Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n = 522, 65.0±8.7 years, 70.3% men). Causal inference was used to reconstruct interactions between SRD5A1 and its downstream targets in liver, using cis-expression Quantitative Trait Loci as instrumental variables. Co-expression networks were constructed with weighted correlation network analysis (WGCNA). Functional enrichment was conducted to determine the roles of target genes. The networks were subsequently validated in an independent cohort of MASLD cases and controls (SteatoSITE; n = 469, 52.5±13.3 years, 52.4% men). We identified 54 cis-eQTLs of SRD5A1 in GTEx and 158 in STARNET liver. At 15% FDR, seven causally regulated genes were found in STARNET, including SERPINF1 and GGPS1, suggesting a role in adiposity and cholesterol metabolism. WGCNA analysis identified 45 modules that were significantly associated with SRD5A1 expression in GTEx and 21 in STARNET. The top two strongly associated modules were enriched for cholesterol and steroid synthesis, and insulin secretion in GTEx; and complement pathways and lipid metabolism in STARNET. Notably, genes within these modules were differentially expressed across fibrosis stages in MASLD patients, with strongest up- or downregulation seen in HMGCS2, APOC1, LIPG, ACAT1, HMGCS1, IL6R, C8B, and ST6GAL1, key genes in the metabolic and inflammatory regulation. Hepatic steatosis and fibrosis induced by disruption of SRD5A1 may be linked with dysregulation in cholesterol metabolism and inflammation pathways in liver. Future work will map the SRD5A1 pathways in subcutaneous and visceral adipose.