Endocrine Abstracts

Low plasma sex hormone-binding globulin (SHBG) levels are present in patients suffering chronic metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, whether altered SHBG production plays a role in development and progression of this disease is unclear. To investigate SHBG involvement in NAFLD, we studied the effects of overexpressing SHBG in two mouse models, a genetically-induced model, by developing a double transgenic mouse by crossing the human SHBG transgenic mouse with the C57BL/ksJ-db/db mouse and a diet-induced model by feeding human SHBG transgenic mice and their WT littermates with high fructose diet (HFrD) during 8 weeks. In addition, HepG2 cells were also used to explore the molecular mechanisms involved on the SHBG role in NAFLD. Moreover, human liver biopsies were used to corroborate the in vivo and in vitro findings. The SHBG overexpression in C57BL/ksJ-db/db mice significantly reduced liver weight and liver fat accumulation by reducing lipogenesis via acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and ATP citrate lyase (ACLY) downregulation. Next we showed that human SHBG transgenic mice were protected against NAFLD induced by HFrD feeding that was evident in their WT littermate mice. The SHBG overexpression in this diet-induced NAFLD mouse model also reduced hepatic lipogenesis via ACC, FAS and ACLY downregulation. Furthermore, we showed a SHBG cell-autonomous effect on hepatocyte lipogenesis since SHBG overexpression reduced total triglyceride content by downregulating ACC mRNA and protein levels in HepG2 cells. Finally, the SHBG expression was inversely correlated with total triglycerides and ACC mRNA levels in human liver biopsies. Overall, we conclude that SHBG is a protective against NAFLD by inhibiting lipogenesis. Therefore, SHBG could be a new therapeutic target whereby increased expression may reduce NAFLD.

Disclosure: This work was supported by two Grants from the Instituto de Salud Carlos III (DMS) CP08/00058, PI09/144, PI12/01357 and CIBER de Diabetes y Enfermedades Metabólicas Asociadas an initiative of Instituto de Salud Carlos III (RF, ABD, CH, AL and DMS).