Possible mechanisms underlying fatty liver in a rat model of male hypogonadism: A protective role for testosterone

• Published in: Steroids 2018-07, Vol.135, p.21-30
• Main Authors: Sakr, Hussein F., Hussein, Abdelaziz M., Eid, Elsayed A., AlKhateeb, Mahmoud
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Body Weight - drug effects; Disease Models, Animal; Fasting - blood; Fatty liver; Gene Expression Regulation - drug effects; Hypogonadism - complications; Insulin - blood; Insulin Resistance; Intra-Abdominal Fat - drug effects; Lipids - blood; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Male hypogonadism; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; Orchidectomy; Organ Size - drug effects; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol Regulatory Element Binding Protein 2 - metabolism; Subcutaneous Fat - drug effects; Testosterone; Testosterone - pharmacology
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2018.04.004

[Display omitted] •ORCD causes visceral obesity, dyslipidemia, impaired GT and insulin resistance.•ORCD increases the activity of liver enzymes that increase TGs and CHOL in liver.•Also, ORCD enhances the hepatic β-oxidation of FAs and oxidative stress in liver.•TRT guards against the visceral obesity and development of NAFLD. Aims: To investigate the effects of testosterone (Test) deficiency and testosterone replacement therapy (TRT) on the development of non-alcoholic fatty liver disease (NAFLD) and associated peripheral insulin resistance (IR) in male rats and to illustrate the underlying mechanisms of action. Materials and methods: male Sprague Dawley rats were divided into 3 groups as follows: 1) sham-operated group (n = 11), 2) ORCD-induced group (n = 9) exposed to orchidectomy (ORCD), achieved by complete surgical removal of testicles, and 3) ORCD + Test treated group (n = 10) (11 ng/mL Test propionate, 3x/week, S.C.). Results: Data revealed significant increases in final body, liver, visceral and subcutaneous fats weights with significant increases in fasting plasma glucose and insulin levels and HOMA-IR. Additionally, ORCD rats had higher UAC for measured glucose levels and insulin levels during OGTT and higher AUC for measured glucose levels during ITT. Interesting, higher serum and hepatic levels of TGs and CHOL and higher serum levels of LDL were seen in ORCD-induced rats. Mechanistically, significant increases in mRNA levels of SREBP-1, SREBP-2, ACC-1, FAS, HMGCOAR and HMGCOAS with significant increases in protein levels of both precursor and mature SREBP-1 and SREBP-2, PPAR-α, p-PPAR-α, CPT-1 and UCP-2 and significant lower protein levels p-AMPK and p-ACC-1 were detected in livers of ORCD rats. Test administration to ORCD-induced rats significantly ameliorated all of the above mentioned biochemical endpoints and reversed the effect of ORCD on mRNA and protein levels of these targets. In conclusion, Test deficiency could be an independent risk factor for the development of NAFLD by upregulation of lipid synthesis and disturb fatty acids oxidation whereas Test therapy is a protective strategy.