Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Simple Summary Hepatocellular carcinoma is a disease with a variety of molecular triggers and is usually reported to prevail in males. However, after the menopause, the disease is also increasing in the female population. Herein, we discovered that chronic depletion of cholesterol synthesis due to the knock-out of the gene Cyp51 from this pathway leads to female prevalent hepatocarcinogenesis in aging mice. There is a high similarity between our mouse model and the situation in humans. Multiple deregulated pathways of hepatocarcinogenesis are shared. A female-dependent metabolic reprogramming leading to this type of liver cancer is exposed for the first time and reflects on deregulated cholesterol synthesis as the metabolic trigger. These data are of crucial importance. Despite the higher overall prevalence of hepatocellular carcinoma in males, we need tools and biomarkers to further stratify patients and offer better diagnosis and treatment options to both sexes. While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14 alpha-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXR alpha:RXR alpha, and importantly, crosstalk between reduced LXR alpha and activated TGF-beta signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPAR alpha were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.