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Project: LiSyM network3
Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer.

Abstract (Expand)

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 14alpha-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, LXRalpha:RXRalpha, and importantly, crosstalk between reduced LXRalpha 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 PPARalpha 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.

Authors: K. B. Cokan, Z. Urlep, G. Lorbek, M. Matz-Soja, C. Skubic, M. Perse, J. Jeruc, P. Juvan, T. Rezen, D. Rozman

Date Published: 9th Nov 2020

Publication Type: Journal

Computational modelling of Hedgehog signalling in liver regeneration

Abstract (Expand)

Organ regeneration is a very complex process that includes not only the reconstruction of organ mass but also the reorganisation of homeostatic capabilities. This especially applies for the liver, which … performs a variety of metabolic functions. In the last decade, morphogenic pathways such as the Wnt/β-Catenin and Hedgehog signalling pathways have been revealed to orchestrate liver regeneration as well as metabolism. Mathematical models have been successfully applied to liver regeneration, but these have not integrated the Hedgehog signalling pathway. In this review it is tried to compile features of Hh signalling in liver regeneration which can be integrated into liver regeneration modeling.

Author: Madlen Matz-Soja

Date Published: 1st Jul 2017

Publication Type: Not specified

Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility

Abstract (Expand)

The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer … therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.

Authors: Christiane Rennert, Franziska Eplinius, Ute Hofmann, Janina Johänning, Franziska Rolfs, Wolfgang Schmidt-Heck, Reinhardt Guthke, Rolf Gebhardt, Albert M. Ricken, Madlen Matz-Soja

Date Published: 30th May 2017

Publication Type: Not specified

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