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 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.

Genes in loci genetically associated with polycystic ovary syndrome are dynamically expressed in human fetal gonadal, metabolic and brain tissues

“…Notably, brothers/sons of women with PCOS have elevated androgen levels ( 53 ), increased total cholesterol and low density lipoproteins levels at puberty ( 16 ), decreased insulin sensitivity (independent of obesity) and glucose tolerance ( 12 ), among other symptoms. Also, hepatic dysfunctions and risk of liver diseases have been observed in PCOS models in male sheep ( 11 ), female sheep ( 54 , 55 ), and rats ( 56 , 57 ), together affirming the roles of these organs in the pathophysiology of the syndrome. Although transcriptional and post-transcriptional factors were not evaluated, INSR and FDFT1 were dynamically expressed in all tissues examined in this study.…”

“…Some of the metabolic symptoms of PCOS have also been observed in male offspring of PCOS mothers in both human and animal studies ( 11 – 16 ). However, the cause of the syndrome still remains unclear.…”

Molecular Research on Polycystic Ovary Syndrome (PCOS)

“…Indeed, first-degree male relatives could present with a male PCOS equivalent, and metabolic disturbances are the main traits. In this regard, Siemienowicz et al [11] examined hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from a PCOS ovine model, to whom testosterone was administrated in order to generate a prenatal androgenic overexposure. Indeed, previous studies supported the association between the latter and PCOS phenotype development in adult life.…”