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Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of “PCOS Males”

Siemienowicz, Katarzyna J.; Filis, Panagiotis; Thomas, Jennifer; Fowler, Paul A.; Duncan, W. Colin; Rae, Mick T.

Authors

Panagiotis Filis

Jennifer Thomas

Paul A. Fowler

W. Colin Duncan



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 the 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 an 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.

Journal Article Type Article
Acceptance Date May 27, 2022
Online Publication Date May 31, 2022
Publication Date 2022
Deposit Date Jun 6, 2022
Publicly Available Date Jun 6, 2022
Journal Biomedicines
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 10
Issue 6
Article Number 1291
DOI https://doi.org/10.3390/biomedicines10061291
Keywords male PCOS; NAFLD; NASH; androgens; prenatal programming; mitochondrial dysfunction; hepatic cholesterol; oxidative phosphorylation; liver fibrosis
Public URL http://researchrepository.napier.ac.uk/Output/2876289

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