Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of "PCOS Males".
Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of "PCOS Males".
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DOI：
10.3390/biomedicines10061291
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发表时间：
2022-05-31
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
多囊卵巢综合征（PCOS）患者的一级男性亲属可能会出现代谢异常，表现为循环胆固醇和甘油三酯升高，提示男性PCOS患者。同样，雄性绵羊在胎儿期过度暴露于过量的雄激素，在青春期出现血脂异常。血脂异常、脂质代谢改变和肝线粒体功能障碍与非酒精性肝病（NAFLD）的发生有关。因此，我们解剖了肝脏线粒体功能和脂质代谢的青春期产前雄激素（PA）男性从绵羊模型PCOS。将替吉奥直接给予雄性绵羊胎仔，以产生产前雄激素过度分泌。肝脏RNA测序和蛋白质组学在6个月大时进行。评估肝脏脂质、糖原、ATP、活性氧（ROS）、DNA损伤和胶原。青少年PA男性的肝胆固醇和糖原积累增加，以及干扰葡萄糖和脂肪酸代谢，线粒体功能障碍，线粒体转运改变，氧化磷酸化和ATP合成减少，线粒体自噬受损。PA男性的线粒体功能障碍与肝脏ROS水平升高和早期肝纤维化体征相关，与NAFLD进展具有临床相关性。我们的结论是，男性胎儿在子宫内雄激素过量暴露导致PCOS样代谢表型，线粒体功能失调，并可能终身健康后遗症。
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.
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DOI：
10.1111/liv.14773
发表时间：
2021-05
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
Allende DS;Gawrieh S;Cummings OW;Belt P;Wilson L;Van Natta M;Behling CA;Carpenter D;Gill RM;Kleiner DE;Yeh MM;Chalasani N;Guy CD;NASH Clinical Research Network
通讯作者：
NASH Clinical Research Network
影响因子：
29.4
作者：
Cotter, Thomas G.;Rinella, Mary
通讯作者：
Rinella, Mary
影响因子：
7.5
作者：
Dabravolski, Siarhei A.;Bezsonov, Evgeny E.;Orekhov, Alexander N.
通讯作者：
Orekhov, Alexander N.
影响因子：
6
作者：
Asimakopoulou, Anastasia;Engel, Kathrin M.;Weiskirchen, Ralf
通讯作者：
Weiskirchen, Ralf
DOI：
10.1017/s2040174417001118
发表时间：
2018-06
影响因子：
1.7
作者：
Barrett ES;Hoeger KM;Sathyanarayana S;Abbott DH;Redmon JB;Nguyen RHN;Swan SH
通讯作者：
Swan SH