Fagman Johan B, Wilhelmson Anna S, Motta Benedetta M, Pirazzi Carlo, Alexanderson Camilla, De Gendt Karel, Verhoeven Guido, Holmäng Agneta, Anesten Fredrik, Jansson John-Olov, Levin Malin, Borén Jan, Ohlsson Claes, Krettek Alexandra, Romeo Stefano, Tivesten Åsa
*Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Physiology, Institute of Neuroscience and Physiology, and Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Nordic School of Public Health, Gothenburg, Sweden; and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
*Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Physiology, Institute of Neuroscience and Physiology, and Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Nordic School of Public Health, Gothenburg, Sweden; and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
FASEB J. 2015 Apr;29(4):1540-50. doi: 10.1096/fj.14-259234. Epub 2014 Dec 30.
Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.
雄激素在男性中具有重要的心脏代谢作用，但其在女性中的代谢作用尚不清楚。为了确定生理性雄激素受体（AR）依赖性雄激素对雌性小鼠动脉粥样硬化发生的作用，我们在易患动脉粥样硬化的载脂蛋白E（apoE）缺陷背景下培育了雌性AR基因敲除（ARKO）小鼠。高脂饮食8周后，而非正常饮食时，ARKO雌性小鼠主动脉中的动脉粥样硬化程度增加（与具有完整AR基因的对照apoE缺陷小鼠相比增加了59%）。它们还表现出体重增加（+18%）、体脂百分比增加（+62%）、肝甘油三酯水平升高、胰岛素敏感性降低以及明显的致动脉粥样硬化性血脂异常（血清胆固醇升高+52%）。在青春期前进行卵巢切除的小鼠中，ARKO小鼠与对照小鼠在动脉粥样硬化、体重和血脂水平上的差异消失，这与卵巢雄激素通过AR介导的保护作用一致。此外，AR激动剂双氢睾酮可降低卵巢切除小鼠的动脉粥样硬化程度（胸主动脉降低41%）、皮下脂肪量（降低44%）和胆固醇水平（降低35%），减少体外肝癌细胞中的肝细胞脂质积累，并调节肝脏中对脂质稳态至关重要的基因的mRNA表达。总之，我们证明AR可保护雌性小鼠免受饮食诱导的动脉粥样硬化，并提出这是通过调节身体组成和脂质代谢介导的。
