» Articles » PMID: 35740312

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

Overview
Journal Biomedicines
Date 2022 Jun 24
PMID 35740312
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

PCOS - the many faces of a disorder in women and men.

Lafci N, Yilmaz B, Yildiz B J Endocrinol Invest. 2024; .

PMID: 39680364 DOI: 10.1007/s40618-024-02512-1.


Molecular Research on Polycystic Ovary Syndrome (PCOS).

Daniele S, Chelucci E, Scarfo G, Artini P Biomedicines. 2023; 11(5).

PMID: 37239028 PMC: 10215849. DOI: 10.3390/biomedicines11051358.


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

Azumah R, Hummitzsch K, Anderson R, Rodgers R Front Endocrinol (Lausanne). 2023; 14:1149473.

PMID: 37223019 PMC: 10201802. DOI: 10.3389/fendo.2023.1149473.


A meta-analysis: Effect of androgens on reproduction in sows.

Guo Z, Lv L, Liu D, Ma H, Radovic C Front Endocrinol (Lausanne). 2023; 14:1094466.

PMID: 36843577 PMC: 9950266. DOI: 10.3389/fendo.2023.1094466.

References
1.
Listenberger L, Han X, Lewis S, Cases S, Farese Jr R, Ory D . Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A. 2003; 100(6):3077-82. PMC: 152249. DOI: 10.1073/pnas.0630588100. View

2.
Caldwell S, Swerdlow R, Khan E, Iezzoni J, Hespenheide E, Parks J . Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999; 31(3):430-4. DOI: 10.1016/s0168-8278(99)80033-6. View

3.
Subramaniam K, Tripathi A, Dabadghao P . Familial clustering of metabolic phenotype in brothers of women with polycystic ovary syndrome. Gynecol Endocrinol. 2019; 35(7):601-603. DOI: 10.1080/09513590.2019.1566451. View

4.
Kasper P, Martin A, Lang S, Kutting F, Goeser T, Demir M . NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2020; 110(7):921-937. PMC: 8238775. DOI: 10.1007/s00392-020-01709-7. View

5.
Cardoso R, Padmanabhan V . Developmental Programming of PCOS Traits: Insights from the Sheep. Med Sci (Basel). 2019; 7(7). PMC: 6681354. DOI: 10.3390/medsci7070079. View