Endocrine Abstracts

Low plasma SHBG is an independent risk factor of cardiovascular disease. Our recent work has shown that SHBG gene expression can be regulated indirectly through HNF4α gene expression. In this regard, we have identified that an increase in hepatic palmitate induced by high carbohydrate diets and pro-inflammatory cytokines (TNFα and IL1β) was able to reduce hepatic HNF4α protein levels which, in turn, decreased SHBG production. The Mediterranean diet, in which olive oil is the primary source of fat, is associated with a lower risk of cardiovascular disease. Since olive oil is the primary source of fat intake, the Mediterranean diet is high in monounsaturated fatty acids (MUFA), specifically oleic acid. The purpose of this study was to investigate the effects of oleic and linoleic acids in the regulation of SHBG production in HepG2 cells and to examine the underlying molecular mechanisms. We provide evidence that oleic acid treatment increased SHBG (mRNA and protein) when compared with linoleic acid treatment over the course of three days in HepG2 cell cultures. Oleic acid and linoleic acid treatment did not change HNF4α (mRNA and protein levels). However, oleic acid treatment reduced PPARγ (mRNA and protein levels), a well-recognized SHBG inhibitor, when compared with linoleic acid treatment. Finally, oleic acid treatment produced a reduction in PPARγ binding and an increase in HNF4α binding to the SHBG promoter when compared with linoleic acid treatment in ChIP assays. In conclusion, our results provide evidence that treatment with oleic acid increases SHBG production, mainly by downregulating PPARγ. Our findings suggest that the effect of oleic acid in increasing SHBG could be a new mechanism involved in the benefitial effect of Mediterranean diet on cardiovascular disease.