Testosterone protects high-fat/low-carbohydrate diet-induced nonalcoholic fatty liver disease in castrated male rats mainly via modulating endoplasmic reticulum stress

• Published in: American Journal of Physiology: Cell Physiology 2018-04, Vol.314 (4), p.E366
• Main Authors: Jia, Yue, Yee, Jennifer K, Wang, Christina, Nikolaenko, Liana, Diaz-Arjonilla, Maruja, Cohen, Joshua N, French, Samuel W, Liu, Peter Y, Lue, YanHe, Lee, Wai-Nang P, Swerdloff, Ronald S
• Format: Article
• Language: English
• Subjects: Carbohydrates; Castration; Endoplasmic reticulum; Fatty liver; High carbohydrate diet; High fat diet; Insulin; Lipids; Liver diseases; Low carbohydrate diet; Low fat diet; NF-κB protein; Nutrient deficiency; Oxidation; Steatosis; Stress proteins; Testosterone
• ISSN: 0363-6143; 1522-1563

We previously showed that testosterone (T) deficiency enhanced high-fat/low-carbohydrate diet (HFD)-induced hepatic steatosis in rats independent of insulin resistance and that T replacement reduced hepatic macrovesicular fat accumulation and inflammation. The present report explores the mechanism of Tʼs protective effects on HFD-induced steatohepatitis. Adult male rats were randomized into four treatment groups for 15 wk: intact rats on regular chow diet or HFD, and castrated rats on HFD with or without T replacement. Fatty acid β-oxidation and de novo synthesis were not changed by castration and T replacement, but expression of lipid export proteins ApoB100 and microsomal triglyceride transfer protein (MTP) was suppressed by HFD in both intact and castrated rats but restored by T replacement. Macrovesicular lipid droplet-related proteins perilipin 1 and fat-specific protein 27 were increased by HFD in castrated rats and suppressed by T replacement. Higher activation/expression of ER stress proteins (PERK, IRE-1α, JNK, NF-κB, and CHOP) was demonstrated in castrated rats fed HFD compared with intact animals, and T replacement suppressed these changes. We conclude that 1) HFD leads to ApoB100/MTP suppression reducing export of lipids; 2) castration promotes progression to steatohepatitis through activation of the ER stress pathway and enhancement of macrovesicular droplet protein expression; and 3) testosterone suppresses ER stress, inhibits the formation of macrovesicular lipid droplets, promotes lipid export, and ameliorates steatohepatitis induced by HFD and castration.