Long-term androgen excess induces insulin resistance and non-alcoholic fatty liver disease in PCOS-like rats. Issue 208 (April 2021)

• Record Type: Journal Article
• Authors: Cui, Peng; Hu, Wei; Ma, Tong; Hu, Min; Tong, Xiaoyu; Zhang, Feifei; Shi, Jiemei; Xu, Xiaoqing; Li, Xin; Shao, Linus Ruijin; Billig, Håkan; Feng, Yi
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 208(2021)
• Publication Date: 2021-04
• Subjects: PCOS polycystic ovary syndrome -- NAFLD non-alcoholic fatty liver disease -- DHT dihydrotestosterone -- Tfam transcription factor A, mitochondrial -- Pgc1α peroxisome proliferator-activated receptor gamma coactivator 1α -- Nrf1 nuclear respiratory factor 1 -- Mfn1 mitofusin-1 -- Opa1 optic atrophy 1 -- Drp1 dynamin-related protein -- OXPHOS oxidative phosphorylation complex -- HSP60 heat shock protein 60 -- SDHA succinate dehydrogenase -- VDAC voltage-dependent anion channel -- PHB1 prohibitin 1 -- SOD1 superoxide dismutase 1 -- Atg autophagy-related protein -- LC3 microtubule-associated protein 1A/1B-light chain 3 (acytosolic LC3-I is conjugated to phosphatidylethanolamine to form LC3-II, which is recruited to autophagosomal membranes) -- AR androgen receptor -- p-MEK1/2 phospho-mitogen-activated protein kinase 1/2 -- p-ERK1/2 phospho-extracellular signal-regulated kinases 1/2 -- ERK1/2 extracellular signal-regulated kinases 1/2 -- p-p90RSK phospho-p90 ribosomal s6 kinase -- RIP3 receptor-interacting serine/threonine-protein kinase 3 -- HMBG1 high-mobility group box 1 -- Bcl2 B-cell lymphoma 2 -- Bcl-xl B-cell lymphoma xl -- Bax bcl2-associated x protein -- Bak Bcl-2 homologous antagonist/killer; Polycystic ovary syndrome -- Non-alcoholic fatty liver disease -- Insulin resistance -- Mitochondria -- Apoptosis -- Autophagy; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2021.105829
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Hyperandrogenism could lead to insulin resistance and hepatic steatosis which was involved in the process of increased lipid synthesis. Mitochondrial dysfunction may be associated with the occurrence of NAFLD in DHT-induced PCOS-like rats. Lipid metabolism disorders and inflammatory response might be partly attributed to the mitochondria-derived imbalance between apoptosis and autophagy. Abstract: Objective: Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51 % of women with PCOS suffer from non-alcoholic fatty liver disease (NAFLD). Investigation into the pathological mechanism behind this association will provide insights for the prevention and treatment of this complication. Methods: Dihydrotestosterone (DHT), a nonaromatic androgen, was used to mimic the pathological conditions of hyperandrogenism and insulin resistance. Hematoxylin and eosin staining, Oil Red O staining, immunofluorescent staining, Western blots, and qRT-PCR were used to verify the hepatic steatosis and inflammation, and the latter two methods were also used for energy and mitochondrion-related assays. ELISA was used to measure the level of reactive oxygen species. Results: Twelve weeks of DHT exposure led to obesity and insulin resistance as well as hepatic steatosis, lipid deposition, and different degrees of inflammation. The expression of molecules involved in respiratory chain and aerobic respiration processes, such as electron transfer complex II, pyruvate dehydrogenase, and succinate dehydrogenase complex subunit A, was inhibited. In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver. Conclusions: Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.