Copyright © 2019 Endocrine Society. Context: There is emerging evidence that SHBG is substantially reduced in chronic metabolic diseases, including obesity and nonalcoholic fatty liver disease (NAFLD). We have recently reported, through use of in vitro (HepG2 cells) and in vivo (SHBG-C57BL/ksJ-db/db mice) models, that SHBG could play a role in arresting the progression of NAFLD by downregulating lipogenesis. Objective: The main aim of this study was to investigate the mechanisms by which SHBG prevents hepatic lipogenesis by examining the relationship between SHBG and a key lipogenic enzyme, such as acetyl-coenzyme A carboxylase (ACC) in the liver of obese persons. Participants and Methods: SHBG and ACC mRNA levels, as well as triglyceride content, were analyzed in 41 liver samples from nondiabetic obese patients with NAFLD who had undergone bariatric surgery. We also studied the effect of SHBG overexpression in HepG2 cells cultured under high-glucose conditions. Results: SHBG mRNA and protein levels were lower in patients with metabolic syndrome than in those without metabolic syndrome; however, these differences were significant only for mRNA level. SHBG mRNA levels correlated positively with SHBG protein levels and hepatic triglyceride content. In addition, SHBG mRNA and protein levels correlated negatively with ACC mRNA levels and triglyceride content. Furthermore, SHBG overexpression abrogated the increase in ACC expression induced by high-glucose treatment in HepG2 cells. Conclusions: Our findings suggest that SHBG plays a role in regulating hepatic lipogenesis by reducing ACC levels. These results suggest a strategy for the treatment of NAFLD.