Endocrine Abstracts

Low plasma SHBG levels are present in patients suffering chronic metabolic diseases, including obesity and non-alcoholic fatty liver disease (NAFLD). In overweight individuals, low plasma SHBG levels are a biomarker for the metabolic syndrome and predict a higher risk of suffering type 2 diabetes and cardiovascular disease. Our recent results demonstrate that SHBG is more than sex hormone carrier and its reduction in obese subjects play an active role in obesity and NAFLD development independently of sex steroids. We have demonstrated these new SHBG actions using different approaches including an in vitro approach, developing different transgenic mouse models and using human samples. Regarding the in vitro approach, we have used HepG2 cells underexpressing and overexpressing SHBG. We have developed a genetically-induced model of obesity and expressing human SHBG (crossing human SHBG transgenic mouse with C57BL/ksJ-db/db mouse), a diet-induced NAFLD model (by feeding human SHBG transgenic mice and their wild-type littermates with high fructose diet (HFrD) during 8 weeks and a diet-induced obesity model by feeding human SHBG transgenic mice and their wild-type littermates with high fat diet (HFD) during 8 weeks. We have elucidated the molecular mechanisms associated by which SHBG protected against NAFLD development and HFD-induced obesity. Moreover, human liver biopsies were used to corroborate the in vivo and in vitro findings. Overall, our results point out to SHBG as a protective factor against obesity and NAFLD. Therefore, SHBG could be a new therapeutic target whereby increased expression may reduce obesity and NAFLD.