Hepatic mitochondrial dysfunction and risk of liver disease in an ovine model of ‘PCOS males

Katarzyna J. Siemienowicz* (Corresponding Author), Panagiotis Filis, Jennifer Thomas, Paul A. Fowler , W. Colin Duncan, Mick T Rae

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

First-degree male relatives of polycystic ovary syndrome (PCOS) sufferers can develop metabolic abnormalities evidenced by elevated circulating cholesterol and triglycerides, suggestive of a male PCOS equivalent. Similarly, male sheep overexposed to excess androgens in fetal life develop dyslipidaemia in adolescence. Dyslipidaemia, altered lipid metabolism and dysfunctional hepatic mitochondria are associated with development of non-alcoholic liver disease (NAFLD). We therefore dissected hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly administered to male ovine fetuses to create prenatal androgenic overexposure. Liver RNA sequencing and proteomics occurred at 6 months of age. Hepatic lipids, glycogen, ATP, reactive oxygen species (ROS), DNA damage and collagen were assessed. Adolescent PA males had increased accumulation of hepatic cholesterol and glycogen, together with perturbed glucose and fatty acid metabolism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phosphorylation and ATP synthesis, and impaired mitophagy. Mitochondrial dysfunction in PA males was associated with increased hepatic ROS level and signs of early liver fibrosis, with clinical relevance to NAFLD progression. We conclude that excess in utero androgen exposure in male fetuses leads to a PCOS-like metabolic phenotype with dysregulated mitochondrial function and likely lifelong health sequelae.
Original languageEnglish
Article number1291
Number of pages22
JournalBiomedicines
Volume10
Issue number6
Early online date31 May 2022
DOIs
Publication statusPublished - 31 May 2022

Keywords

  • Male PCOS
  • NAFLD
  • NASH
  • androgens
  • prenatal programming
  • mitochondrial dysfunction
  • hepatic cholesterol
  • oxidative phosphorylation
  • liver fibrosis

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