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

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 Pmitochondrial function and lipid metabolism in adolescent prena-tally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly adminis-tered 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 metabo-lism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phos-phorylation 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 life-long health sequelae.